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1.	Xie, Xin, et al. (författare) beta-Actin-dependent global chromatin organization and gene expression programs control cellular identity 2018 Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 32:3, s. 1296-1314 Tidskriftsartikel (refereegranskat)abstract During differentiation and development, cell fate and identity are established by waves of genetic reprogramming. Although the mechanisms are largely unknown, during these events, dynamic chromatin reorganization is likely to ensure that multiple genes involved in the same cellular functions are coregulated, depending on the nuclear environment. In this study, using high-content screening of embryonic fibroblasts from a beta-actin knockout (KO) mouse, we found major chromatin rearrangements and changes in histone modifications, such as methylated histone (H)3-lysine-(K)9. Genome-wide H3K9 trimethylation-(Me)3 landscape changes correlate with gene up-and down-regulation in beta-actin KO cells. Mechanistically, we found loss of chromatin association by the Brahma-related gene (Brg)/Brahma-associated factor (BAF) chromatin remodeling complex subunit Brg1 in the absence of beta-actin. This actin-dependent chromatin reorganization was concomitant with the up-regulation of sets of genes involved in angiogenesis, cytoskeletal organization, andmyofibroblast features in beta-actin KO cells. Some of these genes and phenotypes were gained in a beta-actin dose-dependent manner. Moreover, reintroducing a nuclear localization signal-containing beta-actin in the knockout cells affected nuclear features and gene expression. Our results suggest that, by affecting the genome-wide organization of heterochromatin through the chromatin-binding activity of the BAF complex, beta-actin plays an essential role in the determination of gene expression programs and cellular identity.
2.	Almuzzaini, Bader, et al. (författare) In beta-actin knockouts, epigenetic reprogramming and rDNA transcription inactivation lead to growth and proliferation defects 2016 Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 30:8, s. 2860-2873 Tidskriftsartikel (refereegranskat)abstract Actin and nuclear myosin 1 (NM1) are regulators of transcription and chromatin organization. Using a genome-wide approach, we report here that beta-actin binds intergenic and genic regions across the mammalian genome, associated with both protein-coding and rRNA genes. Within the rDNA, the distribution of beta-actin correlated with NM1 and the other subunits of the B-WICH complex, WSTF and SNF2h. In beta-actin(-/-) mouse embryonic fibroblasts (MEFs), we found that rRNA synthesis levels decreased concomitantly with drops in RNA polymerase I (Pol I) and NM1 occupancies across the rRNA gene. Reintroduction of wild-type beta-actin, in contrast to mutated forms with polymerization defects, efficiently rescued rRNA synthesis underscoring the direct role for a polymerization-competent form of beta-actin in Pol I transcription. The rRNA synthesis defects in the beta-actin(-/-) MEFs are a consequence of epigenetic reprogramming with up-regulation of the repressive mark H3K4me1 (mono-methylation of lys4 on histone H3) and enhanced chromatin compaction at promoter-proximal enhancer (T0 sequence), which disturb binding of the transcription factor TTF1. We propose a novel genome-wide mechanism where the polymerase-associated beta-actin synergizes with NM1 to coordinate permissive chromatin with Pol I transcription, cell growth, and proliferation.
3.	Almuzzaini, Bader, et al. (författare) Nuclear myosin 1 contributes to a chromatin landscape compatible with RNA polymerase II transcription activation 2015 Ingår i: BMC Biology. - : Springer Science and Business Media LLC. - 1741-7007. ; 13 Tidskriftsartikel (refereegranskat)abstract Background: Nuclear myosin 1c (NM1) is emerging as a regulator of transcription and chromatin organization. Results: Using chromatin immunoprecipitation and deep sequencing (ChIP-Seq) in combination with molecular analyses, we investigated the global association of NM1 with the mammalian genome. Analysis of the ChIP-Seq data demonstrates that NM1 binds across the entire mammalian genome with occupancy peaks correlating with distributions of RNA Polymerase II (Pol II) and active epigenetic marks at class II gene promoters. In mouse embryonic fibroblasts subjected to RNAi mediated NM1 gene silencing, we show that NM1 synergizes with polymerase-associated actin to maintain active Pol II at the promoter. NM1 also co-localizes with the nucleosome remodeler SNF2h at class II promoters where they assemble together with WSTF as part of the B-WICH complex. A high resolution micrococcal nuclease (MNase) assay and quantitative real time PCR shows that this mechanism is required for local chromatin remodeling. Following B-WICH assembly, NM1 mediates physical recruitment of the histone acetyl transferase PCAF and the histone methyl transferase Set1/Ash2 to maintain and preserve H3K9acetylation and H3K4trimethylation for active transcription. Conclusions: We propose a novel genome-wide mechanism where myosin synergizes with Pol II-associated actin to link the polymerase machinery with permissive chromatin for transcription activation.
4.	Arama, Charles, et al. (författare) Epigenetics and Malaria Susceptibility/Protection : A Missing Piece of the Puzzle 2018 Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9 Forskningsöversikt (refereegranskat)abstract A better understanding of stable changes in regulation of gene expression that result from epigenetic events is of great relevance in the development of strategies to prevent and treat infectious diseases. Histone modification and DNA methylation are key epigenetic mechanisms that can be regarded as marks, which ensure an accurate transmission of the chromatin states and gene expression profiles over generations of cells. There is an increasing list of these modifications, and the complexity of their action is just beginning to be understood. It is clear that the epigenetic landscape plays a fundamental role in most biological processes that involve the manipulation and expression of DNA. Although the molecular mechanism of gene regulation is relatively well understood, the hierarchical order of events and dependencies that lead to protection against infection remain largely unknown. In this review, we propose that host epigenetics is an essential, though relatively under studied, factor in the protection or susceptibility to malaria.
5.	Asp, Patrik, 1968- (författare) Chromatin Remodeling by BRG1 and SNF2H : Biochemistry and Function 2004 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Chromatin is a highly dynamic, regulatory component in the process of transcription, repair, recombination and replication. The BRG1 and SNF2H proteins are ATP-dependent chromatin remodeling proteins that modulate chromatin structure to regulate DNA accessibility for DNA-binding proteins involved in these processes. The BRG1 protein is a central ATPase of the SWI/SNF complexes involved in chromatin remodeling associated with regulation of transcription. SWI/SNF complexes are biochemically hetero-geneous but little is known about the unique functional characteristics of the various forms. We have shown that SWI/SNF activity in SW13 cells affects actin filament organization dependent on the RhoA signaling pathway. We have further shown that the biochemical composition of SWI/SNF complexes qualitatively affects the remodeling activity and that the composition of biochemically purified SWI/SNF complexes does not reflect the patterns of chromatin binding of individual subunits. Chromatin binding assays (ChIP) reveal variations among subunits believed to be constitutive, suggesting that the plasticity in SWI/SNF complex composition is greater than suspected. We have also discovered an interaction between BRG1 and the splicing factor Prp8, linking SWI/SNF activity to mRNA processing. We propose a model whereby parts of the biochemical heterogeneity is a result of function and that the local chromatin environment to which the complex is recruited affect SWI/SNF composition.We have also isolated the novel B-WICH complex that contains WSTF, SNF2H, the splicing factor SAP155, the RNA helicase II/Guα, the transcription factor Myb-binding protein 1a, the transcription factor/DNA repair protein CSB and the RNA processing factor DEK. The formation of this complex is dependent on active transcription and links chromatin remodeling by SNF2H to RNA processing.By linking chromatin remodeling complexes with RNA processing proteins our work has begun to build a bridge between chromatin and RNA, suggesting that factors in chromatin associated assemblies translocate onto the growing nascent RNA.
6.	Asp, Patrik, et al. (författare) Expression of BRG1, a human SWI/SNF component, affects the organisation of actin filaments through the RhoA signalling pathway 2002 Ingår i: Journal of Cell Science. - : Company of Biologists Ltd.. - 0021-9533. ; 115:3, s. 2735-2745 Tidskriftsartikel (refereegranskat)abstract The human BRG1 (brahma-related gene 1) protein is a component of the SWI/SNF family of the ATP-dependent chromatin remodelling complexes. We show here that expression of the BRG1 protein, but not of an ATPase-deficient BRG1 protein, in BRG1-deficient SW13 cells alters the organisation of actin filaments. BRG1 expression induces the formation of thick actin filament bundles resembling stress-fibres, structures that are rarely seen in native SW13 cells. BRG1 expression does not influence the activity state of the RhoA-GTPase, which is involved in stress-fibre formation. We find that RhoA is equally activated by stimuli, such as serum, in BRG1-expressing cells, ATPase-deficient BRG1-expressing cells and native SW13 cells. However, the activation of RhoA by lysophosphatidic acid and serum does not trigger the formation of stress-fibre-like structures in SW13 cells. Activation of the RhoA-GTPase in BRG1-expressing cells induces stress-fibre-like structures, indicating that the BRG1 can couple RhoA activation to stress-fibre formation. At least two downstream effectors are involved in stress-fibre formation, Rho-kinase/ROCK and Dia. BRG1 expression, but not the expression of the ATP-deficient BRG1, increases the protein level of ROCK1, one form of the Rho-kinase/ROCK. That this is of importance is supported by the findings that an increased Rho-kinase/ROCK activity in SW13 cells, obtained by overexpressing wild-type ROCK1 and ROCK2, induces stress-fibre formation. No specificity between the two Rho-kinase/ROCK forms exists. Our results suggest that the BRG1 protein affects the RhoA pathway by increasing the protein level of ROCK1, which allows stress-fibre-like structures to form.
7.	Asp, Patrik, et al. (författare) Variations in subunit composition and chromatin association of mammalian SWI/SNF complexes Annan publikation (övrigt vetenskapligt/konstnärligt)
8.	Attoff, Kristina, 1985-, et al. (författare) Acrylamide alters CREB and retinoic acid signaling pathways during differentiation of the human neuroblastoma SH-SY5Y cell line Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Acrylamide is a known neurotoxic compound that we get exposed to through food and through the environment. It can cross the placental barrier as well as the blood-brain barrier resulting in exposure of the fetus and the infant child. We used the human neuroblastoma cell line SH-SY5Y to study the effects of non-cytotoxic acrylamide exposure during 9 days of differentiation on two differentially important signaling pathways, i.e. the retinoic acid receptor (RAR) and cAMP response element-binding protein (CREB) signaling in neurons. Our results showed that exposure of non-cytotoxic concentrations of acrylamide during 9 days of differentiation induced altered expression of multiple genes that are part of the CREB and RAR activation pathways, e.g. cellular retinoic acid binding protein 1, retinol binding protein 7, CREB5 and fibroblast growth factor receptor 2. Other well-established neuronal markers such as brain-derived neurotrophic factor, syntaxin binding protein 2, transforming growth factor beta 1, the dopaminergic markers monoamine oxidase A and dopamine receptor D2 as wells as the cholinergic marker choline O-acetyltransferase were also significantly altered by acrylamide. Our results reveal that acrylamide interferes with crucial pathways involved in neuronal differentiation in vitro and raise concerns over the potential toxic outcomes in humans.
9.	Attoff, Kristina, 1985- (författare) In vitro developmental neurotoxicity of acrylamide 2016 Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract The number of children with neurodevelopmental disorders is increasing worldwide which makes it a public concern. Exposure to environmental chemicals has been reported as a source of developmental neurotoxicity. There is also an increase in the number of chemicals reaching the global market each year and currently there are thousands of substances that have not yet been tested for developmental neurotoxicity. The current developmental neurotoxicity testing guidelines are time consuming, expensive, require a lot of animals and have relatively low sensitivity understanding for the mechanisms of toxicology. The field of developmental neurotoxicity testing is in need of a paradigm shift to the use of alternative in vitro methods capable of testing and screening large number of substances. The next generation developmental neurotoxicity testing will consist of both in silico and in vitro testing that has to be used in a combined fashion so that it will generate a more rapid and efficient toxicity testing. The methods need to be standardized between laboratories so that reproducible data can be obtained. Simple endpoints will simply not be enough for in vitro developmental neurotoxicity testing models. Rather, a battery of more refined endpoints that pinpoints the specific toxicity of a compound, discriminate between different neural subpopulations and different stages of neural differentiation is crucial for success. The use of mRNA biomarkers could be a good example of such an endpoint, and have been suggested to be valuable in detecting developmental neurotoxicity. This thesis will give a broad overview of different alternative in vitro models for developmental neurotoxicity. Developmental neurotoxicity of acrylamide was investigated by using selected cell models and endpoints. Acrylamide is a well-known neurotoxic compound and most people get exposed to the compound by food consumption and from environmental pollutants. Since acrylamide crosses the placenta barrier, the fetus is also being exposed and the risk for adverse effects in the developing nervous system is overwhelming. The neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y were used to study proliferation and differentiation as indicators for developmental neurotoxicity. The reduced neurite outgrowth in the SH-SY5Y cell model occurred at up to seven orders of magnitude lower than what have been previously shown for different neural cell systems. Acrylamide also affected the differentiation process in both neurons and glia cells in the C17.2 cell line. We show that acrylamide attenuated neural differentiation at seven orders of magnitude lower concentrations than the estimated plasma concentration of free acrylamide in the fetus. The fact that low concentrations seem to delay the differentiation process in both cell lines, raises cause for an alarm for developmental neurotoxicity induced by acrylamide.
10.	Bujila, Ioana, et al. (författare) Exposure to Plasmodium falciparum-derived hemozoin leads to impairment of transcriptional activation upon dendritic cell maturation Annan publikation (övrigt vetenskapligt/konstnärligt)
11.	Bujila, Ioana, et al. (författare) Malaria-derived hemozoin exerts early modulatory effects on the phenotype and maturation of human dendritic cells 2016 Ingår i: Cellular Microbiology. - : Hindawi Limited. - 1462-5814 .- 1462-5822. ; 18:3, s. 413-423 Tidskriftsartikel (refereegranskat)abstract Plasmodium falciparum (P. falciparum)-induced effects on the phenotype of human dendritic cells (DC) could contribute to poor induction of long-lasting protective immunity against malaria. DC ability to present antigens to naïve T cells, thus initiating adaptive immune responses depends on complex switches in chemokine receptors, production of soluble mediators and expression of molecules enabling antigen-presentation and maturation. To examine the cellular basis of these processes in the context of malaria, we performed detailed analysis of early events following exposure of human monocyte-derived DC to natural hemozoin (nHZ) and the synthetic analog of its heme core, β-hematin. DC exposed to either molecule produced high levels of the inflammatory chemokine MCP-1, showed continuous high expression of the inflammatory chemokine receptor CCR5, no upregulation of the lymphoid homing receptor CCR7 and no cytoskeletal actin redistribution with loss of podosomes. DC partially matured as indicated by increased expression of major histocompatibility complex (MHC) class II and CD86 following nHZ and β-hematin exposure, however there was a lack in expression of the maturation marker CD83 following nHZ but not β-hematin exposure. Overall our data demonstrate that exposure to nHZ partially impairs the capacity of DC to mature, an effect in part differential to β-hematin.
12.	Bujila, Ioana, 1983- (författare) Plasmodium falciparum-mediated modulation of innate immune cells: responses and regulation 2016 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Plasmodium falciparum (P. falciparum) infection modulates the response of innate immune cells. The aim of this work was to study the impact of P. falciparum infection and P. falciparum-derived molecules on the response of dendritic cells (DC) and monocytes.In paper I we investigated the effects of natural hemozoin (nHZ), a P. falciparum-derived molecule, on the phenotype and functionality of DC. We found that exposure to nHZ impaired the capacity of DC to mature. Paper II is a follow-up on paper I, where the underlying transcriptional events preceding the nHZ-induced impairment of DC maturation were investigated. More specifically, we examined the involvement of certain transcription factors, subunits of chromatin remodeling complexes and histone modifications in the regulation of DC maturation. Our findings suggest that nHZ-exposure of DC does not lead to recruitment or enrichment of molecules needed for transcriptional activation. In paper III we investigated P. falciparum effects in vivo in sympatric ethnic groups with differential susceptibility towards P. falciparum infection living in Burkina Faso. The aim of this study was to establish the transcriptional networks underlying the relatively better protection against P. falciparum infection observed in the Fulani ethnic group compared to other sympatric ethnic groups. Our findings reveal differential gene expression in monocytes of infected Fulani compared to uninfected Fulani and the difference concerned multiple classes of genes including signal transduction, immunological responses and chromatin remodelers. The results provide new aspects on molecules and regulatory mechanisms that are involved in the relatively more protective response against P. falciparum infection.Taken together, the work presented in this thesis leads to a deeper understanding of the P. falciparum-induced modulation of responses of innate immune cells and the underlying mechanisms possibly regulating those responses.
13.	Bujila, Ioana, et al. (författare) Transcriptome and DNA methylome analysis of two sympatric ethic groups with differential susceptibility to Plasmodium falciparum infection living in Burkina Faso Annan publikation (övrigt vetenskapligt/konstnärligt)
14.	Busayavalasa, Kiran, et al. (författare) The Nup155-mediated organisation of inner nuclear membrane proteins is independent of Nup155 anchoring to the metazoan nuclear pore complex 2012 Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 125:18, s. 4214-4218 Tidskriftsartikel (refereegranskat)abstract The nuclear envelope (NE), an important barrier between the nucleus and the cytoplasm, is composed of three structures: the outer nuclear membrane, which is continuous with the ER, the inner nuclear membrane (INM), which interfaces with chromatin, and nuclear pore complexes (NPCs), which are essential for the exchange of macromolecules between the two compartments. The NPC protein Nup155 has an evolutionarily conserved role in the metazoan NE formation; but the in vivo analysis of Nup155 has been severely hampered by the essential function of this protein in cell viability. Here, we take advantage of the hypomorphicity of RNAi systems and use a combination of protein binding and rescue assays to map the interaction sites of two neighbouring NPC proteins Nup93 and Nup53 on Nup155, and to define the requirements of these interactions in INM protein organization. We show that different parts of Drosophila Nup155 have distinct functions: the Nup155 beta-propeller anchors the protein to the NPC, whereas the alpha-solenoid part of Nup155 is essential for the correct localisation of INM proteins lamin-B receptor (LBR) and otefin. Using chromatin extracts from semisynchronized cells, we also provide evidence that the Nup155 alpha-solenoid has a chromatin-binding activity that is stronger at the end of mitosis. Our results argue that the role of Nup155 in INM protein localisation is not mediated through the NPC anchoring activity of the protein and suggest that regions other than Nup155 beta-propeller are necessary for the targeting of proteins to the INM.
15.	Böhm, Stefanie, 1982- (författare) Non-protein-coding RNA : Transcription and regulation of ribosomal RNA 2014 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Cell growth and proliferation are processes in the cell that must be tightly regulated. Transcription of ribosomal RNA and ribosomal biogenesis are directly linked to cell growth and proliferation, since the ribosomal RNA encodes for the majority of transcription in a cell and ribosomal biogenesis influences directly the number of proteins that are synthesized.In the work presented in this thesis, we have investigated the ribosomal RNA genes, namely the ribosomal DNA genes and the 5S rRNA genes, and their transcriptional regulation. One protein complex that is involved in RNA polymerase I and III transcription is the chromatin remodelling complex B‑WICH (WSTF, SNF2h, NM1). RNA polymerase I transcribes the rDNA gene, while RNA polymerase III transcribes the 5S rRNA gene, among others. In Study I we determined the mechanism by which B‑WICH is involved in regulating RNA polymerase I transcription. B‑WICH is associated with the rDNA gene and was able to create a more open chromatin structure, thereby facilitating the binding of HATs and the subsequent histone acetylation. This resulted in a more active transcription of the ribosomal DNA gene. In Study II we wanted to specify the role of NM1 in RNA polymerase I transcription. We found that NM1 is not capable of remodelling chromatin in the same way as B‑WICH, but we demonstrated also that NM1 is needed for active RNA polymerase I transcription and is able to attract the HAT PCAF. In Study III we investigated the intergenic part of the ribosomal DNA gene. We detected non-coding RNAs transcribed from the intergenic region that are transcribed by different RNA polymerases and that are regulated differently in different stress situations. Furthermore, these ncRNAs are distributed at different locations in the cell, suggesting that they have different functions. In Study IV we showed the involvement of B‑WICH in RNA Pol III transcription and, as we previously had shown in Study I, that B‑WICH is able to create a more open chromatin structure, in this case by acting as a licensing factor for c-Myc and the Myc/Max/Mxd network.Taken together, we have revealed the mechanism by which the B‑WICH complex is able to regulate RNA Pol I and Pol III transcription and we have determined the role of NM1 in the B‑WICH complex. We conclude that B‑WICH is an important factor in the regulation of cell growth and proliferation. Furthermore, we found that the intergenic spacer of the rDNA gene is actively transcribed, producing ncRNAs. Different cellular locations suggest that the ncRNAs have different functions.
16.	Calado Botelho, Salomé, et al. (författare) The association of Brahma with the Balbiani ring 1 gene of Chironomus tentans studied by immunoelectron microscopy and chromatin immunoprecipitation 2008 Ingår i: Insect molecular biology (Print). - : Wiley. - 0962-1075 .- 1365-2583. ; 17:5, s. 505-13 Tidskriftsartikel (refereegranskat)abstract Many steps of gene expression take place during transcription, and important functional information can thus be obtained by determining the distribution of specific factors along a transcribed gene. The Balbiani ring (BR) genes of the dipteran Chironomus tentans constitute a unique system for mapping the association of specific factors along a eukaryotic gene using immuno-electron microscopy (immuno-EM). The chromatin immunoprecipitation (ChIP) technique has provided an alternative, more general method for studying the association of proteins with specific genomic sequences. The immuno-EM and the ChIP methods suffer from different limitations, and thus a combination of both is advantageous. We have established optimal conditions for ChIP on chromatin extracted from the salivary glands of C. tentans, and we have analyzed the association of the SWI/SNF chromatin remodelling factor Brahma (Brm) with the BR1 gene by combined immuno-EM and ChIP. We show that Brm is not restricted to the promoter of the BR1 gene but is also associated with sequences in the middle and distal portions of the gene, which suggests that Brm has additional roles apart from regulating transcription initiation.
17.	Cavellán, Erica, 1966- (författare) Chromatin remodelling in Pol I and III transcription 2006 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Compaction of chromosomes in the eukaryotic cell is due to interactions between DNA and proteins and interactions between proteins. These two types of interaction form a dynamic structure, known as "chromatin". The condensation of chromatin must be carefully regulated, since the structure is an obstacle for factors that need access to the DNA. An extensive range of components, one group of which is the ATP-dependent chromatin remodel-ling complexes, controls the accessibility of DNA. These complexes have been studied in a variety of eukaryotic systems, and their functions in major events in the cell, such as replication, DNA-repair and transcription have been established, as have their roles in the assembly and maintenance of chromatin. All of the complexes contain a highly conserved ATPase, which belongs to the SWI2/SNF2 family of proteins, one group of which is known as the ISWI proteins. There are two forms of ISWI in human, known as "SNF2h" and "SNF2l".We have identified a human SNF2h-assembly, B-WICH, that consists of SNF2h, William’s syndrome transcription factor (WSTF), nuclear myosin (NM1), and a number of additional nuclear proteins including the Myb-binding protein 1a (Myb bp1a), SF3b155/SAP155, the RNA helicase II/Guα, the proto-oncogene Dek, and the Cockayne Syndrome protein B (CSB). The 45S rRNA, 5S rRNA and 7SL RNA are all parts of the B-WICH assembly. The formation of B-WICH depends on active transcription, and is implicated in the regulation of both RNA transcription by both pol I and pol III. The B-WICH provides a link between RNA and the chromatin structure.
18.	Cavellán, Erica, et al. (författare) The WSTF-SNF2h assembly regulates Pol I transcription Annan publikation (övrigt vetenskapligt/konstnärligt)
19.	Cavellán, Erica, et al. (författare) WSTF-SNF2h interacts ith several nuclear proteins in a transcription dependent manner, to form a functional unit B-WICH Annan publikation (övrigt vetenskapligt/konstnärligt)
20.	Ciesla, Malgorzata, et al. (författare) Fructose bisphosphate aldolase is involved in the control of RNA polymerase III-directed transcription 2014 Ingår i: Biochimica et Biophysica Acta. Molecular Cell Research. - : Elsevier BV. - 0167-4889 .- 1879-2596. ; 1843:6, s. 1103-1110 Tidskriftsartikel (refereegranskat)abstract Yeast Fba1 (fructose 1,6-bisphosphate aldolase) is a glycolytic enzyme essential for viability. The overproduction of Fba1 enables overcoming of a severe growth defect caused by a missense mutation rpc128-1007 in a gene encoding the 028 protein, the second largest subunit of the RNA polymerase III complex. The suppression of the growth phenotype by Fbal is accompanied by enhanced de novo tRNA transcription in rpc128-1007 cells. We inactivated residues critical for the catalytic activity of Fbal. Overproduction of inactive aldolase still suppressed the rpc128-1007 phenotype, indicating that the function of this glycolytic enzyme in RNA polymerase III transcription is independent of its catalytic activity. Yeast Fbal was determined to interact with the RNA polymerase III complex by coimmunoprecipitation. Additionally, a role of aldolase in control of tRNA transcription was confirmed by ChIP experiments. The results indicate a novel direct relationship between RNA polymerase HI transcription and aldolase.
21.	Eberle, Andrea B., et al. (författare) The use of a synthetic DNA-antibody complex as external reference for chromatin immunoprecipitation 2012 Ingår i: Analytical Biochemistry. - : Elsevier BV. - 0003-2697 .- 1096-0309. ; 426:2, s. 147-152 Tidskriftsartikel (refereegranskat)abstract Chromatin immunoprecipitation (ChIP) is an analytical method used to investigate the interactions between proteins and DNA in vivo. ChIP is often used as a quantitative tool, and proper quantification relies on the use of adequate references for data normalization. However, many ChIP experiments involve analyses of samples that have been submitted to experimental treatments with unknown effects, and this precludes the choice of suitable internal references. We have developed a normalization method based on the use of a synthetic DNA-antibody complex that can be used as an external reference instead. A fixed amount of this synthetic DNA-antibody complex is spiked into the chromatin extract at the beginning of the ChIP experiment. The DNA-antibody complex is isolated together with the sample of interest, and the amounts of synthetic DNA recovered in each tube are measured at the end of the process. The yield of synthetic DNA recovery in each sample is then used to normalize the results obtained with the antibodies of interest. Using this approach, we could compensate for losses of material, reduce the variability between ChIP replicates, and increase the accuracy and statistical resolution of the data.
22.	Gañez Zapater, Antoni, 1986- (författare) Gene regulation by chromatin remodelling complexes : SWI/SNF complex in mRNA processing and B-WICH complex in ribosomal gene expression 2018 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The aim of this project is to investigate the roles of chromatin remodelling complexes in gene regulation. It is focused on two groups of chromatin complexes: the mammalian BRG1 and BRM SWI/SNF complexes and the ISWI-containing B-WICH complex.Study 1 investigates the role of SWI/SNF complexes in alternative splicing. We show that the presence of the ATPase core subunits Brg1 and Brm influence the alternative splicing outcome of a subset of genes. We show that Brg1 and Brm interact with several splicing related factors in the nascent RNA, and that the recruitment of some of these factors to their target sites is regulated by the presence of Brg1 and Brm. We propose that SWI/SNF ATPases can modulate the interactions of RNA binding factors to the nascent RNA and in that way alter alternative splicing outcome.Study 2 focuses on SWI/SNF complexes and their influence on cleavage and polyadenylation of mRNA. We show that Brg1 and Brm interact with subunits of the cleavage and polyadenylation complexes in the nascent mRNA. SWI/SNF complexes facilitate the recruitment of the cleavage and polyadenylation complex to the polyadenylation site in a subset of genes, and this results in a more efficient cleavage and polyadenylation.Study 3 shows that B-WICH is required for ribosome gene transcriptional activation upon glucose stimulation. WSTF and SNF2h, two of the B-WICH subunits, are needed to establish an active chromatin state in the RNA pol I gene promoter when the glucose concentration is raised after a period of deprivation. We propose that it counteracts the silent, poised chromatin state imposed by the silencing chromatin remodelling complex NuRD to allow for the RNA pol I machinery to bind to the promoter.These studies show that the influence of chromatin remodelling complexes upon gene expression is important for remodelling nucleosomes at the promoter, for alternative splicing, cleavage and polyadenylation and transcriptional initiation. These complexes work together with other chromatin remodelling factors, interact with other complexes and regulate their activity by affecting their recruitment dynamics.
23.	Gañez Zapater, Antoni, 1986-, et al. (författare) SWI/SNF subunits Brg1 and Brm regulate alternative splicing by interacting with RNA binding proteins in the nascent RNA. Annan publikation (övrigt vetenskapligt/konstnärligt)
24.	Gañez-Zapater, Antoni, 1986-, et al. (författare) The SWI/SNF subunit BRG1 affects alternative splicing by changing RNA binding factor interactions with nascent RNA 2022 Ingår i: Molecular Genetics and Genomics. - : Springer Science and Business Media LLC. - 1617-4615 .- 1617-4623. ; 297:2, s. 463-484 Tidskriftsartikel (refereegranskat)abstract BRG1 and BRM are ATPase core subunits of the human SWI/SNF chromatin remodelling complexes mainly associated with transcriptional initiation. They also have a role in alternative splicing, which has been shown for BRM-containing SWI/SNF complexes at a few genes. Here, we have identified a subset of genes which harbour alternative exons that are affected by SWI/SNF ATPases by expressing the ATPases BRG1 and BRM in C33A cells, a BRG1- and BRM-deficient cell line, and analysed the effect on splicing by RNA sequencing. BRG1- and BRM-affected sub-sets of genes favouring both exon inclusion and exon skipping, with only a minor overlap between the ATPase. Some of the changes in alternative splicing induced by BRG1 and BRM expression did not require the ATPase activity. The BRG1-ATPase independent included exons displayed an exon signature of a high GC content. By investigating three genes with exons affected by the BRG-ATPase-deficient variant, we show that these exons accumulated phosphorylated RNA pol II CTD, both serine 2 and serine 5 phosphorylation, without an enrichment of the RNA polymerase II. The ATPases were recruited to the alternative exons, together with both core and signature subunits of SWI/SNF complexes, and promoted the binding of RNA binding factors to chromatin and RNA at the alternative exons. The interaction with the nascent RNP, however, did not reflect the association to chromatin. The hnRNPL, hnRNPU and SAM68 proteins associated with chromatin in cells expressing BRG1 and BRM wild type, but the binding of hnRNPU to the nascent RNP was excluded. This suggests that SWI/SNF can regulate alternative splicing by interacting with splicing-RNA binding factor and influence their binding to the nascent pre-mRNA particle.
25.	Guo, Yuan, 1989- (författare) RNA Polymerase I regulation by chromatin remodelling 2020 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Cell proliferation and growth is correlated with effective protein synthesis and ribosome biogenesis. The transcription of the 47S pre-ribosomal RNA by RNA Polymerase I (RNA Pol I) machinery is the rate-limiting step of ribosome biogenesis and can accounts for more than 50% of total cellular transcription. RNA Polymerase I transcription is a highly energy-consuming process which requires regulation at various stages.In the work presented in this thesis, we have investigated the regulation of RNA Pol I transcription, and investigated the stress response triggered by impaired RNA Pol I transcription. We showed in study I that the ATP dependent chromatin remodelling complex B-WICH is required to maintain an open chromatin landscape at the ribosomal DNA (rDNA) gene promoter in order to allow for transcription initiation by RNA Pol I. In absence of B-WICH, the NuRD complex reconfigures the chromatin landscape to an inaccessible state. We showed in study II that impairment of RNA Pol I transcription by deleting WSTF, a core subunit of B-WICH resulted in cell cycle arrest and apoptosis. More severe inhibition of RNA Pol I transcription through chemical compounds resulted in activation of cellular stress response cascades including but not limited to cell cycle arrest, unfolded protein response and oxidative stress response. We showed in study III that RNA Pol I transcription was increased during epithelial-mesenchymal transition (EMT) in the context of development and disease. The association of the EMT-driving transcription factor SNAIL1 with the rDNA gene promoter was shown to be essential in EMT triggered RNA Pol I transcription. The work presented in this thesis demonstrates the importance of RNA Pol I transcription regulation in maintaining cellular homeostasis.
26.	Jordán-Pla, Antonio, et al. (författare) SWI/SNF regulates half of its targets without the need of ATP-driven nucleosome remodeling by Brahma 2018 Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 19 Tidskriftsartikel (refereegranskat)abstract Background: Brahma (BRM) is the only catalytic subunit of the SVVI/SNF chromatin-remodeling complex of Drosophila melanogaster. The function of SWI/SNF in transcription has long been attributed to its ability to remodel nucleosomes, which requires the ATPase activity of BRM. However, recent studies have provided evidence for a non-catalytic function of BRM in the transcriptional regulation of a few specific genes.Results: Here we have used RNA-seq and ChIP-seq to identify the BRM target genes in 52 cells, and we have used a catalytically inactive BRM mutant (K804R) that is unable to hydrolyze ATP to investigate the magnitude of the non-catalytic function of BRM in transcription regulation. We show that 49% of the BRM target genes in 52 cells are regulated through mechanisms that do not require BRM to have an ATPase activity. We also show that the catalytic and non-catalytic mechanisms of SVVI/SNF regulation operate on two subsets of genes that differ in promoter architecture and are linked to different biological processes.Conclusions: This study shows that the non-catalytic role of SWI/SNF in transcription regulation is far more prevalent than previously anticipated and that the genes that are regulated by SVVI/SNF through ATPase-dependent and ATPase-independent mechanisms have specialized roles in different cellular and developmental processes.
27.	Kiesler, Eva, et al. (författare) The Hrp65 self-interaction is mediated by an evolutionarily conserved domain and is required for nuclear import of Hrp65 isoforms that lack a nuclear localization signal 2003 Ingår i: Journal of Cell Science. - : Company of Biologists. - 1477-9137 .- 0021-9533. ; 116:19, s. 3949-3956 Tidskriftsartikel (refereegranskat)abstract Hrp65, an evolutionary conserved RNA-binding protein from the midge Chironomus tentans, has a conserved DBHS (Drosophila behavior, human splicing) domain that is also present in several mammalian proteins. In a yeast two-hybrid screening we found that Hrp65 can interact with itself. Here we confirm the Hrp65 self-interaction by in vitro pull-down experiments and map the sequences responsible for the interaction to a region that we refer to as the protein-binding domain located within the DBHS domain. We also show that the protein-binding domains of Drosophila NonA and human PSF, two other proteins with conserved DBHS domains, bind to Hrp65 in the yeast two-hybrid system. These observations indicate that the protein-binding domain can mediate homodimerization of Hrp65 as well as heterodimerization between different DBHS-containing proteins. Moreover, analyses of recombinant Hrp65 by gel-filtration chromatography show that Hrp65 can not only dimerize but also oligomerize into complexes of at least three to six molecules. Furthermore, we have analyzed the functional significance of the Hrp65 self-interaction in cotransfection assays, and our results suggest that the interaction between different Hrp65 isoforms is crucial for their intracellular localization.
28.	Lasaviciute, Gintare, et al. (författare) Gut commensal Limosilactobacillus reuteri induces atypical memory-like phenotype in human dendritic cells in vitro 2022 Ingår i: Gut microbes. - : Informa UK Limited. - 1949-0976 .- 1949-0984. ; 14:1 Tidskriftsartikel (refereegranskat)abstract Memory-like responses in innate immune cells confer nonspecific protection against secondary exposures. A number of microbial agents have been found to induce enhanced or diminished recall responses in innate cells, however, studies investigating the ability of probiotic bacteria to trigger such effects are lacking. Here, we show that priming of human monocytes with a secretome from the gut probiotic bacterium Limosilactobacillus (L.) reuteri induces a mixed secondary response phenotype in monocyte-derived dendritic cells (mo-DCs), with a strong IL-6 and IL-1β response but low TNFα, IL-23 and IL-27 secretion. Instead, blood DC priming with L. reuteri-secretome resembles a tolerant state upon secondary exposure. A similar pattern was found in conventional and gut-like (retinoic acid exposed) DCs, although retinoic acid hampered TNFα and IL-6 production and enrichment of histone modifications in L. reuteri-secretome primed mo-DC cultures. Further, we show that the memory-like phenotype of mo-DCs, induced by priming stimuli, is important for subsequent T helper (Th) cell differentiation pathways and might determine the inflammatory nature of Th cells. We also show enhanced recall responses characterized by robust inflammatory cytokines and lactate production in the gut-like mo-DCs derived from β-glucan primed monocytes. Such responses were accompanied with enriched histone modifications at the promoter of genes associated with a trained phenotype in myeloid cells. Altogether, we demonstrate that a gut commensal-derived secretome prompts recall responses in human DCs which differ from that induced by classical training agents such as β-glucan. Our results could be beneficial for future therapeutic interventions where T cell responses are needed to be modulated.
29.	Lindström, Helena (författare) Equine glutathione transferase A3-3 : an efficient steroid isomerase 2018 Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract Glutathione transferases (GSTs) comprise a superfamily of enzymes prominently involved in detoxication by making toxic electrophiles more polar and therefore more easily excretable. However some GSTs have developed alternative functions. Thus, a member of the Alpha class GSTs in tissues of the ruminants, Sus scrofa and Homo sapiens is involved in biosynthesis of steroid hormones, catalyzing a double-bond isomerization reaction as the last step of synthesis of Δ4-pregnene-3,20-dione (progesterone) and the obligatory step in the synthesis of the last precursor of testosterone, Δ4-androstenene-3,17-dione. As neurosteroids, steroid hormones are involved in such diverse functions as cognition, depression and memory and are suggested to play a protective role in neuropathologies including Alzheimer’s disease, Parkinson’s disease and brain injury.The human GST A3-3 is the most efficient steroid double-bond isomerase known so far in mammals. The current work extends discoveries of GST enzymes that act in the steroidogenic pathways in large mammals to Equus ferus caballus. In contrast to the rodents, Equus ferus caballus shares the steroidogenic pathway with Homo sapiens, which makes it a more suitable model for human steroidogenesis than the murine one.In the present study, the mRNA encoding the steroid isomerase GST A3-3 was cloned from stallion testis. The equine GST A3-3 (EcaGST A3-3) was heterologously expressed in E. coli and purified by centrifugation, sonication, affinity chromatography and dialysis. The in vitro measurements of enzymatic activity were followed spectrophotometrically and revealed highly efficient steroid double-bond isomerase activity in the biosynthetic pathways to progesterone and testosterone. The enzyme now ranks as one of the most efficient steroid isomerases known in mammals.The concentrations of EcaGSTA3 mRNA were highest in hormone-producing organs such as ovary, testis and adrenal gland. The high efficiency and the tissue distribution of EcaGST A3-3 support the view that the enzyme plays a physiologically significant role in the biosynthesis of steroid hormones.Inhibition of EcaGST A3-3 might help treat reproductive and neurodegenerative disorders. An FDA-approved library of 1040 compounds was screened for novel inhibitors of EcaGST A3-3. The inhibition pattern of EcaGST A3-3 is similar to that of the human GST A3-3.
30.	Lundqvist, Jessica (författare) Estimation of acute toxicity by using the differentiated neuronal progenitor C17.2 cell model 2017 Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract The authorities in Europe and United States request information regarding possible toxicity for substances that are produced in one tonne or more per year. Estimation of acute systemic toxicity is conducted in vivo using mice or rats. These tests can be time consuming, costly, unethical, and in some cases irrelevant due to the lack of similarity between humans and rodents. It has been proposed that determining general cytotoxicity together with more tissue-specific effects assessed by using in vitro test systems, e.g. reflecting adverse structure or function in the nervous system, can be an alternative approach to the in vivo tests. Neurotoxicity studies in vitro can be performed by using primary cell cultures from fresh tissue or established cell lines, the latter being often preferred as they are beneficial both economically and ethically.Here, I present a murine neural progenitor cell line called C17.2 with the potential to differentiate to a mixed culture of both neurons and astrocytes. The differentiation process was examined using 3 different media compositions and 3 different exposures, totally 9 different scenarios. After 7 days in culture with DMEM/F-12 medium containing N2 supplements and 10 ng/mL nerve growth factor and 10 ng/mL brain derived neurotrophic factor, the culture contained two morphological distinguishable cell types, assumed to be neurons and astrocytes. Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) and Western blot analyses were performed which confirmed the presence of neurons and astrocytes in the differentiated cultures. The mRNA and protein levels of the neuronal marker bIII-tubulin and the astrocyte marker glial fibrillary acidic protein (GFAP) were up-regulated during differentiation, while the progenitor cell marker nestin was down-regulated.To further investigate how this differentiated neural cell model responded to neurotoxic and non-neurotoxic substances, cell membrane potential (CMP) and mRNA expression of bIII-tubulin, GFAP and heat shock protein-32 were examined after exposure to nicotine, atropine, strychnine, ethanol, digoxin, and acetylsalicylic acid. The concentrations that induced effects on the CMP and biomarker expression were compared to general cytotoxicity (Inhibitory Concentration 50%) determined by the neutral red uptake assay in a mouse fibroblast 3T3 cell line, i.e. the 3T3/NRU assay. The CMP assay showed that nicotine, atropine and strychnine exposure induced depolarisation of the cell membrane. However, no effect on the CMP was seen when the cells were treated with acetylsalicylic acid, digoxin, and ethanol at non-cytotoxic concentrations. Alternation in the mRNA expression levels for one of the three biomarkers was seen at non-cytotoxic concentrations for all the compounds that induced acute toxicity by neuronal modes of action, i.e. nicotine, atropine and strychnine. No significant alteration was seen in any of the biomarker mRNA levels when the differentiated C17.2 cells were exposed to compounds that do not induce acute toxicity by neuronal modes of action, i.e. digoxin and acetylsalicylic acid and ethanol.In conclusion, acute toxicity, which could be induced by neuronal modes of action, may be detected in the differentiated C17.2 cell model by using CMP and gene expression biomarkers as endpoints. The simple cell culture requirements for culturing and differentiating the C17.2 cells into a mixed culture of neurons and astrocytes, the robustness in toxicity read-out, and the cost-effectiveness of the assay make the C17.2 cell line attractive as a model for acute neurotoxicity studies.
31.	Maiga, Bakary (författare) Human candidate polymorphisms and malaria susceptibility in sympatric ethnic groups, The Fulani and The Dogon of Mali 2014 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract In malaria endemic regions, resistance to malaria constitutes a critical selective pressureon genetic polymorphisms that regulate immune defense and inflammatory pathways.Differences in malaria susceptibility between sympatric ethnic groups have been described inMali. The Fulani are less susceptible to malaria compared to the neighboring group the Dogon,in spite of similar socio-economic and environmental conditions.Paper I is focused on IL-4-590 T/C polymorphism and correlation with levels of malariaspecific IgG, IgG (1-4) subclasses as well as malaria specific and total IgE level in the two ethnicgroups. Our data show that the Fulani individual carrying the IL-4-590 T allele found to havehigher parasite carriage rate and had higher levels of malaria-specific IgG4 and IgE compared tothe individual carrying the C allele. No such differences were seen within the Dogon.Paper II investigated 166 SNPs in the human host in individuals belonging to the Fulani and theDogon ethnic groups. These SNPs were correlated with total IgG against AMA-1, MSP-1, MSP-2 and CSP antigens as well as total IgE level. All antibody levels were higher in the Fulanicompared to the Dogon and strengthens previous finding that antibodies might play a role in theprotection seen in the Fulani. We identified higher frequencies of the protective blood group O.Several allelic differences between the two ethnic groups were found in CD36, IL-4, RTN3 andADCY9. Moreover several polymorphisms in SLC22A4, IRF1, IL5, LTA and TNF have beenfound to be correlated with anti-MSP antibody level; TLR6, IL3, TNF, and IL22 found to becorrelated with anti-MSP-2 antibody level in the Fulani. Such association was not seen in theDogon.In Paper III, the same individuals, as in paper II, were investigated with a focus on the FcγRIIapolymorphism and correlation with levels of anti-AMA-1, MSP-1, MSP-2, CSP specificantibodies as well as total IgE level. The genotype distribution and allele frequency weresignificantly different between the Fulani and the Dogon with the Fulani being HH, H allele- andthe Dogon RR, R allele carriers. A correlation between the HH genotype and the H allele andprotection against mild malaria was seen in the Fulani but not in the DogonTaken together our study has found significant genetic differences between the Fulani and theDogon Ethnic groups, which suggest that ethnicity should be taken into account in monitoring ofimmunological studies and vaccines trials in malaria endemic areas.
32.	Niss, Frida (författare) RNA binding proteins and epigenetics in SCA7 2019 Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract Polyglutamine diseases are a group of nine disorders that includes, among others SCA7. The common denominator is an expanded glutamine tract in the respective disease protein caused by unstable replication during meiosis. Most research within this field points to a combination of gain-of-function and loss-of-function mechanisms causing all polyglutamine diseases. Using a SCA7 model we are thus attempting to study both of these mechanisms. The glutamine tract expansion responsible for SCA7 is located in the protein Ataxin-7, which like the other polyglutamine proteins aggregates into large inclusions in patient cells. In a gain-of-function mechanism, the aggregates are suggested to cause stress to the cell by e.g. sequestering vital proteins into the aggregates, which could disrupt their function. RNA-binding proteins such as FUS and TDP-43 are often found in aggregates in neurodegenerative diseases, and have been observed in SCA7 aggregates as well. However, if disruption of FUS and TDP-43 function occurs, or if it plays a role in SCA7 pathology is unclear. We found a high rate of co-aggregation of FUS with Ataxin-7 using immunofluorescence and filter trap assays. Furthermore, we found that both the localization and function of FUS was altered in a SCA7 cell model using cell fractionations and RT-PCR. Additionally, we found that TDP-43 also co-aggregated with Ataxin-7 and phosphorylation of TDP-43 was increased during the disease phenotype.Wild-type Ataxin-7 normally functions within chromatin regulation processes, and loss-of-function pathology in SCA7 could therefore involve a disruption of these processes. We have developed a method, FRIC, that enables us to study chromatin organization in live cells using confocal microscopy and fluorescently tagged histones. Using inhibitors of HATs and HDACs, as well as a previously known protein that regulates chromatin structure, we were able to observe changes in chromatin structure in the nuclear periphery, confirming the usefulness of FRIC. Additionally, we investigated the involvement of an inner nuclear membrane protein, Samp1, in chromatin organization and found Samp1 to be instrumental in organizing peripheral chromatin.Taken together, the results from these two studies indicate that SCA7 pathology disturbs RNA-binding protein mediated transcriptional regulation in a gain-of-function mechanism, and that FRIC is a powerful new tool for examining chromatin regulation in diseases with disrupted transcription, like SCA7.
33.	Percipalle, Pergiorgio, et al. (författare) The chromatin remodelling complex WSTF-SNF2h interacts with nuclear myosin 1 and serves a role in RNA polymerase I transcription 2006 Ingår i: EMBO reports. - 1469-3178. ; :March, 3 Tidskriftsartikel (refereegranskat)
34.	Prakash, Varsha, et al. (författare) Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease 2019 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10 Tidskriftsartikel (refereegranskat)abstract Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ER alpha) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.
35.	Quin, Jaclyn E., et al. (författare) Major transcriptional changes observed in the Fulani, an ethnic group less susceptible to malaria 2017 Ingår i: eLIFE. - 2050-084X. ; 6 Tidskriftsartikel (refereegranskat)abstract The Fulani ethnic group has relatively better protection from Plasmodium falciparum malaria, as reflected by fewer symptomatic cases of malaria, lower infection rates, and lower parasite densities compared to sympatric ethnic groups. However, the basis for this lower susceptibility to malaria by the Fulani is unknown. The incidence of classic malaria resistance genes are lower in the Fulani than in other sympatric ethnic populations, and targeted SNP analyses of other candidate genes involved in the immune response to malaria have not been able to account for the observed difference in the Fulani susceptibility to P.falciparum. Therefore, we have performed a pilot study to examine global transcription and DNA methylation patterns in specific immune cell populations in the Fulani to elucidate the mechanisms that confer the lower susceptibility to P.falciparum malaria. When we compared uninfected and infected Fulani individuals, in contrast to uninfected and infected individuals from the sympatric ethnic group Mossi, we observed a key difference: a strong transcriptional response was only detected in the monocyte fraction of the Fulani, where over 1000 genes were significantly differentially expressed upon P.falciparum infection.
36.	Rolicka, Anna, et al. (författare) The chromatin remodelling complex B-WICH is required for transcriptional activation of the ribosomal transcription by glucose stimulation. Annan publikation (övrigt vetenskapligt/konstnärligt)
37.	Ryme, Jessica, et al. (författare) Variations in the Composition of Mammalian SWI/SNF Chromatin Remodelling Complexes 2009 Ingår i: Journal of Cellular Biochemistry. - : Wiley. - 0730-2312 .- 1097-4644. ; 108:3, s. 565-576 Tidskriftsartikel (refereegranskat)abstract The ATP-dependent chromatin remodelling complexes SWI/SNF alter the chromatin structure in transcriptional regulation. Several classes of mammalian SWI/SNF complex have been isolated biochemically, distinguished by a few specific subunits, such as the BAF-specific BAF250A, BAF250B and BRM, and the PBAF-specific BAF 180. We have determined the complex compositions using low stringency immunoprecipitation (IP) and shown that the pattern of subunit interactions was more diverse than previously defined classes had predicted. The subunit association at five gene promoters that depend on the SWI/SNF activity varied and the sequential chromatin immunoprecipitations revealed that different class-specific subunits occupied the promoters at the same time. The low-stringency IP showed that the BAF-specific BAF250A and BAF250B and the PBAF-specific BAF180 co-exist in a subset of SWI/SNF complexes, and fractionation of nuclear extract on size-exclusion chromatography demonstrated that sub-complexes with unorthodox subunit compositions were present in the cell. We propose a model in which the constellations of SWI/SNF complexes are ""tailored"" for each specific chromatin target and depend on the local chromatin environment to which complexes and sub-complexes are recruited.
38.	Sabri, Nafiseh, et al. (författare) Evidence for a posttranscriptional role of a TFIIICalpha-like protein in Chironomus tentans 2002 Ingår i: Molecular Biology of the Cell. - : American Society for Cell Biology (ASCB). - 1059-1524 .- 1939-4586. ; 13:5, s. 1765-1777 Tidskriftsartikel (refereegranskat)abstract We have cloned and sequenced a cDNA that encodes for a nuclear protein of 238 kDa in the dipteran Chironomus tentans. This protein, that we call p2D10, is structurally similar to the alpha subunit of the general transcription factor TFIIIC. Using immunoelectron microscopy we have shown that a fraction of p2D10 is located at sites of transcription, which is consistent with a possible role of this protein in transcription initiation. We have also found that a large fraction of p2D10 is located in the nucleoplasm and in the nuclear pore complexes. Using gel filtration chromatography and coimmunoprecipitation methods, we have identified and characterized two p2D10-containing complexes that differ in molecular mass and composition. The heavy p2D10-containing complex contains at least one other component of the TFIIIC complex, TFIIIC-epsilon. Based on its molecular mass and composition, the heavy p2D10-containing complex may be the Pol III holoenzyme. The light p2D10-containing complex contains RNA together with at least two proteins that are thought to be involved in mRNA trafficking, RAE1 and hrp65. The observations reported here suggest that this new TFIIIC-alpha-like protein is involved in posttranscriptional steps of premRNA metabolism in Chironomus tentans.
39.	Sadeghifar, Fatemeh, 1969- (författare) Regulation of RNA polymerase I and RNA polymerase III transcription by the chromatin remodelling complex B-WICH 2012 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Ribosomal biogenesis is an important process which determines the rate of cell growth and is involved in cell response to proliferation, differentiation, cellular nutritional state and stress. The chromatin remodelling complex B-WICH composed of WSTF, SNF2h and NM1 is involved in transcription by the RNA pol I and RNA pol III. In this study I investigated the mechanism by which the B-WICH complex modulates the RNA pol I and RNA pol III transcription. I showed that B-WICH binds to the 45S genes, 5S rRNA and 7SL RNA genes, and remodels the chromatin. The remodelling at the 45S genes occurs at the promoter, leading higher accessibility to histone acetyltransferases, such as PCAF and p300. In the RNA pol III transcription, the chromatin outside of the gene is more open, leading to binding of c-Myc, with the subsequent recruitment of histone acetylation resulting in H3-Ac. The importance of the chromatin remodelling around the genes was particularly clear in WSTF knock-down cells, in which the binding of RNA pol III and auxiliary transcription factors at the 5S rRNA and 7SL RNA gene promoters were totally abolished. I concluded that B-WICH functions in a similar manner on both RNA pol I and RNA pol III genes, remodels chromatin locally at the promoter and around the genes, which allows other factors to bind. I also investigated the role of B-WICH in the control of RNA pol I transcription, in the cell cycle and in response to glucose/energy status. My results showed that the B-WICH complex disassembled in prophase, and reassembled at G1. WSTF is hyperphosphorylated in mitosis, and with the dephosphorylation at the end of telophase, the SNF2h and NM1 bind to the WSTF. A reduction of the association of the B-WICH complex is seen in cells treated with inhibitors of different signalling pathways. Furthermore, during glucose deprivation, the level of B-WICH decreases at the RNA pol I promoter. These results demonstrate that the chromatin remodelling complex B-WICH is important in the transcription of RNA pol I and RNA pol III genes, as maintaining the chromatin state in an active configuration.
40.	Sadeghifar, Fatemeh, 1969-, et al. (författare) The B-WICH chromatin-remodelling complex facilitates the binding of c-Myc and histone acetyl transferases and regulates RNA pol III transcription Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Transcription of the 5S rRNA genes and 7SL genes by RNA polymerase III is necessary for cell growth and proliferation. The chromatin-remodelling complex B-WICH is associated with these genes, and siRNA-silencing of one component, the WSTF protein, reduces the level of transcription. However, the molecular mechanism is unclear. We show here that the role of B-WICH is to promote the binding of RNA polymerase III and RNA polymerase III factors, TFIIIA, TFIIIB and TFIIIC. WSTF knock down by siRNA resulted in a decreased recruitment of these initiation factors and, consequently, RNA polymerase III, to promoters. In addition, B-WICH induced a local alteration of the chromatin structure around the 5S rRNA and 7SL RNA genes, leading to a reduced acetylation of histone H3, in particular H3K9-Ac. A reduction in the level of WSTF also caused a loss of c-myc binding to the genes. We propose a model in which B-WICH complex is required to maintain an open chromatin structure around these RNA polymerase III genes, a prerequisite for other factors to associate at the gene.
41.	Sadeghifar, Fatemeh, et al. (författare) The B-WICH chromatin-remodelling complex regulates RNA polymerase III transcription by promoting Max-dependent c-Myc binding 2015 Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 43:9, s. 4477-4490 Tidskriftsartikel (refereegranskat)abstract The chromatin-remodelling complex B-WICH, comprised of William syndrome transcription factor, the ATPase SNF2h and nuclear myosin, specifically activates RNA polymerase III transcription of the 5S rRNA and 7SL genes. However, the underlying mechanism is unknown. Using high-resolution MN walking we demonstrate here that B-WICH changes the chromatin structure in the vicinity of the 5S rRNA and 7SL RNA genes during RNA polymerase III transcription. The action of B-WICH is required for the binding of the RNA polymerase machinery and the regulatory factors c-Myc at the 5S rRNA and 7SL RNA genes. In addition to the c-Myc binding site at the 5S genes, we have revealed a novel c-Myc and Max binding site in the intergenic spacer of the 5S rDNA. This region also contains a region remodelled by B-WICH. We demonstrate that c-Myc binds to both sites in a Max-dependent way, and thereby activate transcription by acetylating histone H3. The novel binding patterns of c-Myc and Max link transcription of 5S rRNA to the Myc/Max/Mxd network. Since B-WICH acts prior to c-Myc and other factors, we propose a model in which the B-WICH complex is required to maintain an open chromatin structure at these RNA polymerase III genes. This is a prerequisite for the binding of additional regulatory factors.
42.	Stefanie, Böhm, et al. (författare) Non-coding RNAs from the rDNA intergenic repeat are transcribed by RNA polymerase I and II and have different functions Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Long intergenic non-coding RNA, linc RNA, are often produced from intergenic sequences and have been ascribed diverse functions, such as regulating mRNA levels and being involved in the formation of heterochromatin. We show here that the intergenic spacer region (IGS) of the ribosomal DNA gene repeat in human cells is transcribed. Three ncRNAs, the IGS19asRNA, the IGS32asRNA and the IGS38RNA, of 500, 800 and 1300 bases, respectively, were isolated and investigated. Two of them, the IGS19asRNA and the IGS32asRNA, were transcribed in the antisense direction with respect to the rRNA and in the sense direction for the IGS38RNA. We also showed that the ncRNAs were transcribed by different RNA polymerases; the IGS19asRNA and the IGS38RNA were transcribed by RNA polymerase II and the IGS32asRNA were transcribed by RNA polymerase I. The three ncRNAs were also differentially regulated; IGS19asRNA induced upon heat shock and the level of the IGS32asRNA increased upon glucose feeding, similar to the 45S rRNA. In addition, the ncRNAs IGS19asRNA and IGS32asRNA were found at different locations in the nucleus, with IGS19asRNA located in a speckled pattern in the nucleus and IGS32asRNA associated with chromatin bound to heterochromatin protein 1. This suggests that the IGS32asRNA has a role in heterochromatin formation.
43.	Tariq, Kanwal, et al. (författare) Antagonising Chromatin Remodelling Activities in the Regulation of Mammalian Ribosomal Transcription 2021 Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 12:7 Forskningsöversikt (refereegranskat)abstract Ribosomal transcription constitutes the major energy consuming process in cells and is regulated in response to proliferation, differentiation and metabolic conditions by several signalling pathways. These act on the transcription machinery but also on chromatin factors and ncRNA. The many ribosomal gene repeats are organised in a number of different chromatin states; active, poised, pseudosilent and repressed gene repeats. Some of these chromatin states are unique to the 47rRNA gene repeat and do not occur at other locations in the genome, such as the active state organised with the HMG protein UBF whereas other chromatin state are nucleosomal, harbouring both active and inactive histone marks. The number of repeats in a certain state varies on developmental stage and cell type; embryonic cells have more rRNA gene repeats organised in an open chromatin state, which is replaced by heterochromatin during differentiation, establishing different states depending on cell type. The 47S rRNA gene transcription is regulated in different ways depending on stimulus and chromatin state of individual gene repeats. This review will discuss the present knowledge about factors involved, such as chromatin remodelling factors NuRD, NoRC, CSB, B-WICH, histone modifying enzymes and histone chaperones, in altering gene expression and switching chromatin states in proliferation, differentiation, metabolic changes and stress responses.
44.	Troye-Blomberg, Marita, et al. (författare) What will studies of Fulani individuals naturally exposed to malaria teach us about protective immunity to malaria? 2020 Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 92:4 Forskningsöversikt (refereegranskat)abstract There are an estimated over 200 million yearly cases of malaria worldwide. Despite concerted international effort to combat the disease, it still causes approximately half a million deaths every year, the majority of which are young children with Plasmodium falciparum infection in sub-Saharan Africa. Successes are largely attributed to malaria prevention strategies, such as insecticide-treated mosquito nets and indoor spraying, as well as improved access to existing treatments. One important hurdle to new approaches for the treatment and prevention of malaria is our limited understanding of the biology of Plasmodium infection and its complex interaction with the immune system of its human host. Therefore, the elimination of malaria in Africa not only relies on existing tools to reduce malaria burden, but also requires fundamental research to develop innovative approaches. Here, we summarize our discoveries from investigations of ethnic groups of West Africa who have different susceptibility to malaria.
45.	Vintermist, Anna, 1980- (författare) Chromatin remodelling of ribosomal genes - be bewitched by B-WICH 2015 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Transcription of the ribosomal genes accounts for the majority of transcription in the cell due to the constant high demand for ribosomes. The number of proteins synthesized correlates with an effective ribosomal biogenesis, which is regulated by cell growth and proliferation. In the work presented in this thesis, we have investigated the ribosomal RNA genes 45S and 5S rRNA, which are transcribed by RNA Pol I and RNA Pol III, respectively.The focus of this work is the chromatin remodelling complex B-WICH, which is composed of WSTF, the ATPase SNF2h and NM1. We have studied in particular its role in ribosomal gene transcription. We showed in Study I that B-WICH is required to set the stage at rRNA gene promoters by remodelling the chromatin into an open, transcriptionally active configuration. This results in the binding of histone acetyl transferases to the genes and subsequent histone acetylation, which is needed for ribosomal gene activation. Study II investigated the role of B-WICH in transcription mediated by RNA polymerase III. We showed that B-WICH is essential to create an accessible chromatin atmosphere at 5S rRNA genes, which is compatible with the results obtained in Study 1. In this case, however, B-WICH operates as a licensing factor for c-Myc and the Myc/Max/Mxd network. Study III confirmed the importance and the function of the B-WICH complex as an activator of ribosomal genes. We demonstrated that B-WICH is important for the remodelling of the rDNA chromatin into an active, competent state in response to extracellular stimuli, and that the association of the B-WICH complex to the rRNA gene promoter is regulated by proliferative and metabolic changes in cells.The work presented in this thesis has confirmed that the B-WICH complex is an important regulator and activator of Pol I and Pol III transcription. We conclude that B-WICH is essential for remodelling the rDNA chromatin into a transcriptionally active state, as required for efficient ribosomal gene transcription.
46.	Vintermist, Anna, et al. (författare) The Chromatin Remodelling Complex B-WICH Changes the Chromatin Structure and Recruits Histone Acetyl-Transferases to Active rRNA Genes 2011 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4 Tidskriftsartikel (refereegranskat)abstract The chromatin remodelling complex B-WICH, which comprises the William syndrome transcription factor (WSTF), SNF2h, and nuclear myosin 1 (NM1), is involved in regulating rDNA transcription, and SiRNA silencing of WSTF leads to a reduced level of 45S pre-rRNA. The mechanism behind the action of B-WICH is unclear. Here, we show that the B-WICH complex affects the chromatin structure and that silencing of the WSTF protein results in a compaction of the chromatin structure over a 200 basepair region at the rRNA promoter. WSTF knock down does not show an effect on the binding of the rRNA-specific enhancer and chromatin protein UBF, which contributes to the chromatin structure at active genes. Instead, WSTF knock down results in a reduced level of acetylated H3-Ac, in particular H3K9-Ac, at the promoter and along the gene. The association of the histone acetyl-transferases PCAF, p300 and GCN5 with the promoter is reduced in WSTF knock down cells, whereas the association of the histone acetyl-transferase MOF is retained. A low level of H3-Ac was also found in growing cells, but here histone acetyl-transferases were present at the rDNA promoter. We propose that the B-WICH complex remodels the chromatin structure at actively transcribed rRNA genes, and this allows for the association of specific histone acetyl-transferases.
47.	Vintermist, Anna, et al. (författare) The chromatin remodelling complex B-WICH is required for transcriptional activation by glucose stimulation Annan publikation (övrigt vetenskapligt/konstnärligt)
48.	von Walden, Ferdinand, et al. (författare) Mechanical loading induces the expression of a Pol I regulon at the onset of skeletal muscle hypertrophy 2012 Ingår i: American Journal of Physiology - Cell Physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 302:10, s. c1523-C1530 Tidskriftsartikel (refereegranskat)abstract von Walden F, Casagrande V, Ostlund Farrants AK, Nader GA. Mechanical loading induces the expression of a Pol I regulon at the onset of skeletal muscle hypertrophy. Am J Physiol Cell Physiol 302: C1523-C1530, 2012. First published March 7, 2012; doi:10.1152/ajpcell.00460.2011.-The main goal of the present study was to investigate the regulation of ribosomal DNA (rDNA) gene transcription at the onset of skeletal muscle hypertrophy. Mice were subjected to functional overload of the plantaris by bilateral removal of the synergist muscles. Mechanical loading resulted in muscle hypertrophy with an increase in rRNA content. rDNA transcription, as determined by 45S pre-rRNA abundance, paralleled the increase in rRNA content and was consistent with the onset of the hypertrophic response. Increased transcription and protein expression of c-Myc and its downstream polymerase I (Pol I) regulon (POL1RB, TIF-1A, PAF53, TTF1, TAF1C) was also consistent with the increase in rRNA. Similarly, factors involved in rDNA transcription, such as the upstream binding factor and the Williams syndrome transcription factor, were induced by mechanical loading in a corresponding temporal fashion. Chromatin immunoprecipitation revealed that these factors, together with Pol I, were enriched at the rDNA promoter. This, in addition to an increase in histone H3 lysine 9 acetylation, demonstrates that mechanical loading regulates rRNA synthesis by inducing a gene expression program consisting of a Pol I regulon, together with accessory factors involved in transcription and chromatin remodeling at the rDNA promoter. Altogether, these data indicate that transcriptional and epigenetic mechanisms take place in the regulation of ribosome production at the onset of muscle hypertrophy.
49.	Waldholm, Johan, et al. (författare) SWI/SNF regulates the alternative processing of a specific subset of pre-mRNAs in Drosophila melanogaster 2011 Ingår i: BMC Molecular Biology. - : Springer Science and Business Media LLC. - 1471-2199. ; 12 Tidskriftsartikel (refereegranskat)abstract Background: The SWI/SNF chromatin remodeling factors have the ability to remodel nucleosomes and play essential roles in key developmental processes. SWI/SNF complexes contain one subunit with ATPase activity, which in Drosophila melanogaster is called Brahma (Brm). The regulatory activities of SWI/SNF have been attributed to its influence on chromatin structure and transcription regulation, but recent observations have revealed that the levels of Brm affect the relative abundances of transcripts that are formed by alternative splicing and/or polyadenylation of the same pre-mRNA.Results: We have investigated whether the function of Brm in pre-mRNA processing in Drosophila melanogaster is mediated by Brm alone or by the SWI/SNF complex. We have analyzed the effects of depleting individual SWI/SNF subunits on pre-mRNA processing throughout the genome, and we have identified a subset of transcripts that are affected by depletion of the SWI/SNF core subunits Brm, Snr1 or Mor. The fact that depletion of different subunits targets a subset of common transcripts suggests that the SWI/SNF complex is responsible for the effects observed on pre-mRNA processing when knocking down Brm. We have also depleted Brm in larvae and we have shown that the levels of SWI/SNF affect the pre-mRNA processing outcome in vivo.Conclusions: We have shown that SWI/SNF can modulate alternative pre-mRNA processing, not only in cultured cells but also in vivo. The effect is restricted to and specific for a subset of transcripts. Our results provide novel insights into the mechanisms by which SWI/SNF regulates transcript diversity and proteomic diversity in higher eukaryotes.
50.	Yu, Simei, 1988- (författare) ATPase dependent and independent roles of Brahma in transcription and pre-mRNA processing 2015 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract SWI/SNF is a chromatin-remodeling complex and Brahma (BRM) is the ATPase subunit of SWI/SNF. BRM regulates transcription by remodeling the nucleosomes at promoter regions. BRM is also associated with RNA and affects pre-mRNA processing together with other SWI/SNF subunits. In this thesis, I will discuss the roles of BRM in both transcription and pre-mRNA processing. In Paper I, we showed that BRM, as well as other SWI/SNF subunits SNR1 and MOR, affects the alternative processing of a subset of pre-mRNAs, as shown by microarray analysis. This observation was validated by RNAi experiments both in Drosophila S2 cells and in vivo. In Paper II, we characterized the trans-splicing of transcripts derived from the mod(mdg4) gene. RNA interference (RNAi) and overexpression experiments revealed that BRM regulates the trans-splicing of mod(mdg4)-RX in an ATPase independent manner. In Paper III, we analyzed the expression of two BRM-target genes identified in Paper I, CG44250 and CG44251. RNAi and overexpression experiments showed that the expression levels of these two genes were affected by BRM in a manner that is independent of its ATPase activity. Transcriptome analysis further proved that BRM affects gene expression both in ATPase dependent and independent manners. In Paper IV, we showed that BRM is present at the 3’-end of two analyzed genes, CG5174 and CG2051. BRM facilitates the recruitment of the cleavage and polyadenylation machinery to the cleavage sites through protein-protein interactions that do not require the ATPase activity of BRM. Morevoer, BRM promotes the cleavage of the CG5174 and CG2051 pre-mRNAs. To sum up, SWI/SNF plays important roles not only in transcription but also in pre-mRNA processing. To regulate transcription, BRM can either act as an ATPase-dependent chromatin remodeler or in a manner that does not involve ATPase activity. Additionally, BRM interacts with RNA-binding proteins to regulate the processing of a subset of pre-mRNAs, and this function of BRM is independent of its chromatin remodeling activity.

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