| 1. |
- Ravasi, Timothy, et al.
(författare)
-
An Atlas of Combinatorial Transcriptional Regulation in Mouse and Man
- 2010
-
Ingår i: CELL. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 140:5, s. 744-752
-
Tidskriftsartikel (refereegranskat)abstract
- Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution.
|
|
| 2. |
- Acevedo, Nathalie, et al.
(författare)
-
Epigenetic alterations in skin homing CD4(+)CLA(+) T cells of atopic dermatitis patients
- 2020
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- T cells expressing the cutaneous lymphocyte antigen (CLA) mediate pathogenic inflammation in atopic dermatitis (AD). The molecular alterations contributing to their dysregulation remain unclear. With the aim to elucidate putative altered pathways in AD we profiled DNA methylation levels and miRNA expression in sorted T cell populations -(CD4(+), -CD4(+)CD45RA(+) naive, -CD4(+)CLA(+), and -CD8(+)) from adult AD patients and healthy controls (HC). Skin homing -CD4(+)CLA(+) T cells from AD patients showed significant differences in DNA methylation in 40 genes compared to HC (p < 0.05). Reduced DNA methylation levels in the upstream region of the interleukin-13 gene (IL13) in -CD4(+)CLA(+) T cells from AD patients correlated with increased IL13 mRNA expression in these cells. Sixteen miRNAs showed differential expression in -CD4(+)CLA(+) T cells from AD patients targeting genes in 202 biological processes (p < 0.05). An integrated network analysis of miRNAs and CpG sites identified two communities of strongly interconnected regulatory elements with strong antagonistic behaviours that recapitulated the differences between AD patients and HC. Functional analysis of the genes linked to these communities revealed their association with key cytokine signaling pathways, MAP kinase signaling and protein ubiquitination. Our findings support that epigenetic mechanisms play a role in the pathogenesis of AD by affecting inflammatory signaling molecules in skin homing -CD4(+)CLA(+) T cells and uncover putative molecules participating in AD pathways.
|
|
| 3. |
- Einarsdottir, Elisabet, et al.
(författare)
-
A preliminary transcriptome analysis suggests a transitory effect of vitamin D on mitochondrial function in obese young Finnish subjects
- 2019
-
Ingår i: Endocrine Connections. - : Bioscientifica. - 2049-3614. ; 8:5, s. 559-570
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The effect of vitamin D at the transcriptome level is poorly understood, and furthermore, it is unclear if it differs between obese and normal-weight subjects. The objective of the study was to explore the transcriptome effects of vitamin D supplementation. Design and methods: We analysed peripheral blood gene expression using GlobinLock oligonucleotides followed by RNA sequencing in individuals participating in a 12-week randomised double-blinded placebo-controlled vitamin D intervention study. The study involved 18 obese and 18 normal-weight subjects (of which 20 males) with mean (+/- s.D.) age 20.4 (+/- 2.5) years and BMIs 36 (+/- 10) and 23 (+/- 4) kg/m(2), respectively. The supplemental daily vitamin D dose was 50 mu g (2000 IU). Data were available at baseline, 6- and 12-week time points and comparisons were performed between the vitamin D and placebo groups separately in obese and normal-weight subjects. Results: Significant transcriptomic changes were observed at 6 weeks, and only in the obese subjects: 1724 genes were significantly upregulated and 186 genes were downregulated in the vitamin D group compared with placebo. Further analyses showed several enriched gene categories connected to mitochondrial function and metabolism, and the most significantly enriched pathway was related to oxidative phosphorylation (adjusted P value 3.08 x 10(-14)). Taken together, our data suggest an effect of vitamin D supplementation on mitochondrial function in obese subjects. Conclusions: Vitamin D supplementation affects gene expression in obese, but not in normal-weight subjects. The altered genes are enriched in pathways related to mitochondrial function. The present study increases the understanding of the effects of vitamin D at the transcriptome level.
|
|
| 4. |
- Kack, Ulrika, et al.
(författare)
-
Nasal upregulation of CST1 in dog-sensitised children with severe allergic airway disease
- 2021
-
Ingår i: ERJ Open Research. - : European Respiratory Society (ERS). - 2312-0541. ; 7:2
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The clinical presentation of children sensitised to dog dander varies from asymptomatic to severe allergic airway disease, but the genetic mechanisms underlying these differences are not clear. The objective of the present study was to investigate nasal transcriptomic profiles associated with dog dander sensitisation in school children and to reveal clinical symptoms related with these profiles. Methods: RNA was extracted from nasal epithelial cell brushings of children sensitised to dog dander and healthy controls. Blood sample analyses included IgE against dog dander, dog allergen molecules, other airborne and food allergens, basophil activation and white blood cell counts. Clinical history of asthma and rhinitis was recorded, and lung function was assessed (spirometry, methacholine provocation and exhaled nitric oxide fraction). Results: The most overexpressed gene in children sensitised to dog dander compared to healthy controls was CST1, coding for Cystatin 1. A cluster of these children with enhanced CST1 expression showed lower forced expiratory volume in 1 s, increased bronchial hyperreactivity, pronounced eosinophilia and higher basophil allergen threshold sensitivity compared with other children sensitised to dog dander. In addition, multi-sensitisation to lipocalins was more common in this group. Conclusions: Overexpression of CST1 is associated with more severe allergic airway disease in children sensitised to dog dander. CST1 is thus a possible biomarker of the severity of allergic airway disease and a possible therapeutic target for the future treatment of airborne allergy.
|
|
| 5. |
- Kobayashi, Shintaro, et al.
(författare)
-
Linear Trimer Formation with Antiferromagnetic Ordering in 1 T-CrSe2 Originating from Peierls-like Instabilities and Interlayer Se-Se Interactions
- 2019
-
Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 58:21, s. 14304-14315
-
Tidskriftsartikel (refereegranskat)abstract
- Anomalous successive structural transitions in layered 1T-CrSe 2 with an unusual Cr 4+ valency were investigated by synchrotron X-ray diffraction. 1T-CrSe 2 exhibits dramatic structural changes in in-plane Cr-Cr and interlayer Se-Se distances, which originate from two interactions: (i) in-plane Cr-Cr interactions derived from Peierls-like trimerization instabilities on the orbitally assisted one-dimensional chains and (ii) interlayer Se-Se interactions through p-p hybridization. As a result, 1T-CrSe 2 has the unexpected ground state of an antiferromagnetic metal with multiple Cr linear trimers with three-center-two-electron σ bonds. Interestingly, partial substitution of Se for S atoms in 1T-CrSe 2 changes the ground state from an antiferromagnetic metal to an insulator without long-range magnetic ordering, which is due to the weakening of interlayer interactions between anions. The unique low-temperature structures and electronic states of this system are determined by the competition and cooperation of in-plane Cr-Cr and interlayer Se-Se interactions.
|
|
| 6. |
- Koel, Mariann, et al.
(författare)
-
Human endometrial cell-type-specific RNA sequencing provides new insights into the embryo-endometrium interplay
- 2022
-
Ingår i: HUMAN REPRODUCTION OPEN. - : Oxford University Press (OUP). - 2399-3529. ; 2022:4
-
Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION: Which genes regulate receptivity in the epithelial and stromal cellular compartments of the human endometrium, and which molecules are interacting in the implantation process between the blastocyst and the endometrial cells? SUMMARY ANSWER: A set of receptivity-specific genes in the endometrial epithelial and stromal cells was identified, and the role of galectins (LGALS1 and LGALS3), integrin beta 1 (ITGB1), basigin (BSG) and osteopontin (SPP1) in embryo-endometrium dialogue among many other protein-protein interactions were highlighted. WHAT IS KNOWN ALREADY: The molecular dialogue taking place between the human embryo and the endometrium is poorly understood due to ethical and technical reasons, leaving human embryo implantation mostly uncharted. STUDY DESIGN, SIZE, DURATION: Paired pre-receptive and receptive phase endometrial tissue samples from 16 healthy women were used for RNA sequencing. Trophectoderm RNA sequences were from blastocysts. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cell-type-specific RNA-seq analysis of freshly isolated endometrial epithelial and stromal cells using fluorescence-activated cell sorting (FACS) from 16 paired pre-receptive and receptive tissue samples was performed. Endometrial transcriptome data were further combined in silico with trophectodermal gene expression data from 466 single cells originating from 17 blastocysts to characterize the first steps of embryo implantation. We constructed a protein-protein interaction network between endometrial epithelial and embryonal trophectodermal cells, and between endometrial stromal and trophectodermal cells, thereby focusing on the very first phases of embryo implantation, and highlighting the molecules likely to be involved in the embryo apposition, attachment and invasion. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 499 epithelial and 581 stromal genes were up-regulated in the receptive phase endometria when compared to pre-receptive samples. The constructed protein-protein interactions identified a complex network of 558 prioritized protein-protein interactions between trophectodermal, epithelial and stromal cells, which were grouped into clusters based on the function of the involved molecules. The role of galectins (LGALS1 and LGALS3), integrin beta 1 (ITGB1), basigin (BSG) and osteopontin (SPP1) in the embryo implantation process were highlighted. LARGE SCALE DATA: RNA-seq data are available at www.ncbi.nlm.nih.gov/geo under accession number GSE97929. LIMITATIONS, REASONS FOR CAUTION: Providing a static snap-shot of a dynamic process and the nature of prediction analysis is limited to the known interactions available in databases. Furthermore, the cell sorting technique used separated enriched epithelial cells and stromal cells but did not separate luminal from glandular epithelium. Also, the use of biopsies taken from non-pregnant women and using spare IVF embryos (due to ethical considerations) might miss some of the critical interactions characteristic of natural conception only. WIDER IMPLICATIONS OF THE FINDINGS: The findings of our study provide new insights into the molecular embryo-endometrium interplay in the first steps of implantation process in humans. Knowledge about the endometrial cell-type-specific molecules that co-ordinate successful implantation is vital for understanding human reproduction and the underlying causes of implantation failure and infertility. Our study results provide a useful resource for future reproductive research, allowing the exploration of unknown mechanisms of implantation. We envision that those studies will help to improve the understanding of the complex embryo implantation process, and hopefully generate new prognostic and diagnostic biomarkers and therapeutic approaches to target both infertility and fertility, in the form of new contraceptives.
|
|
| 7. |
- Pirttiniemi, Anniina, et al.
(författare)
-
Long-chain polyphosphates inhibit type I interferon signaling and augment LPS-induced cytokine secretion in human leukocytes.
- 2023
-
Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 114:3, s. 250-265
-
Tidskriftsartikel (refereegranskat)abstract
- Inorganic polyphosphates are evolutionarily conserved bioactive phosphate polymers found as various chain lengths in all living organisms. In mammals, polyphosphates play a vital role in the regulation of cellular metabolism, coagulation, and inflammation. Long-chain polyphosphates are found along with endotoxins in pathogenic gram-negative bacteria and can participate in bacterial virulence. We aimed to investigate, whether exogenously administered polyphosphates modulate human leukocyte function in vitro by treating the cells with three different chain lengths of polyphosphates (P14, P100, and P700). The long-chain polyphosphates, P700, had a remarkable capacity to downregulate type I interferon signaling dose dependently in THP1-Dual cells while only a slight elevation could be observed in the NF-κB pathway with the highest dose of P700. P700 treatment decreased LPS-induced IFNβ transcription and secretion, STAT1 phosphorylation, and downregulated subsequent interferon stimulated gene expression in primary human peripheral blood mononuclear cells. P700 also augmented LPS-induced secretion of IL-1α, IL-1β, IL-4, IL-5, IL-10, and IFNγ. Furthermore, P700 has previously been reported to increase the phosphorylation of several intracellular signaling mediators, such as AKT, mTOR, ERK, p38, GSK3α/β, HSP27, and JNK pathway components, which was supported by our findings. Taken together, these observations demonstrate the extensive modulatory effects P700 has on cytokine signaling, and the inhibitory effects specifically targeted to type I interferon signaling in human leukocytes.
|
|
| 8. |
- Sjögren, Rasmus J. O., et al.
(författare)
-
Branched-chain amino acid metabolism is regulated by ERRα in primary human myotubes and is further impaired by glucose loading in type 2 diabetes
- 2021
-
Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 64:9, s. 2077-2091
-
Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Increased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes pathogenesis. However, most metabolomic studies are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a metabolic challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism is partially unknown. This study aimed to identify differences in circulating and skeletal muscle BCAA levels in response to an OGTT in individuals with normal glucose tolerance (NGT) or type 2 diabetes. Additionally, transcription factors involved in the regulation of the BCAA gene set were identified.Methods: Plasma and vastus lateralis muscle biopsies were obtained from individuals with NGT or type 2 diabetes before and after an OGTT. Plasma and quadriceps muscles were harvested from skeletal muscle-specific Ppargc1a knockout and transgenic mice. BCAA-related metabolites and genes were assessed by LC-MS/MS and quantitative RT-PCR, respectively. Small interfering RNA and adenovirus-mediated overexpression techniques were used in primary human skeletal muscle cells to study the role of PPARGC1A and ESRRA in the expression of the BCAA gene set. Radiolabelled leucine was used to analyse the impact of oestrogen-related receptor α (ERRα) knockdown on leucine oxidation.Results: Impairments in BCAA catabolism in people with type 2 diabetes under fasting conditions were exacerbated after a glucose load. Branched-chain keto acids were reduced 37–56% after an OGTT in the NGT group, whereas no changes were detected in individuals with type 2 diabetes. These changes were concomitant with a stronger correlation with glucose homeostasis biomarkers and downregulated expression of branched-chain amino acid transaminase 2, branched-chain keto acid dehydrogenase complex subunits and 69% of downstream BCAA-related genes in skeletal muscle. In primary human myotubes overexpressing peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α, encoded by PPARGC1A), 61% of the analysed BCAA genes were upregulated, while 67% were downregulated in the quadriceps of skeletal muscle-specific Ppargc1a knockout mice. ESRRA (encoding ERRα) silencing completely abrogated the PGC-1α-induced upregulation of BCAA-related genes in primary human myotubes. Conclusions/interpretation: Metabolic inflexibility in type 2 diabetes impacts BCAA homeostasis and attenuates the decrease in circulating and skeletal muscle BCAA-related metabolites after a glucose challenge. Transcriptional regulation of BCAA genes in primary human myotubes via PGC-1α is ERRα-dependent. Graphical abstract: [Figure not available: see fulltext.]
|
|
| 9. |
- Tobiasson, Magnus, et al.
(författare)
-
Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease
- 2017
-
Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:17, s. 28812-28825
-
Tidskriftsartikel (refereegranskat)abstract
- Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median beta-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.
|
|
| 10. |
- Valta, Milla, et al.
(författare)
-
Viral infection-related gene upregulation in monocytes in children with signs of β-cell autoimmunity
- 2022
-
Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 23:6, s. 703-713
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The pathogenesis of type 1 diabetes (T1D) is associated with genetic predisposition and immunological changes during presymptomatic disease. Differences in immune cell subset numbers and phenotypes between T1D patients and healthy controls have been described; however, the role and function of these changes in the pathogenesis is still unclear. Here we aimed to analyze the transcriptomic landscapes of peripheral blood mononuclear cells (PBMCs) during presymptomatic disease. Methods: Transcriptomic differences in PBMCs were compared between cases positive for islet autoantibodies and autoantibody negative controls (9 case–control pairs) and further in monocytes and lymphocytes separately in autoantibody positive subjects and control subjects (25 case–control pairs). Results: No significant differential expression was found in either data set. However, when gene set enrichment analysis was performed, the gene sets “defence response to virus” (FDR <0.001, ranking 2), “response to virus” (FDR <0.001, ranking 3) and “response to type I interferon” (FDR = 0.002, ranking 12) were enriched in the upregulated genes among PBMCs in cases. Upon further analysis, this was also seen in monocytes in cases (FDR = 0.01, ranking 2; FDR = 0.04, ranking 3 and FDR = 0.02, ranking 1, respectively) but not in lymphocytes. Conclusion: Gene set enrichment analysis of children with T1D-associated autoimmunity revealed changes in pathways relevant for virus infection in PBMCs, particularly in monocytes. Virus infections have been repeatedly implicated in the pathogenesis of T1D. These results support the viral hypothesis by suggesting altered immune activation of viral immune pathways in monocytes during diabetes.
|
|
| 11. |
- Wedenoja, Satu, et al.
(författare)
-
Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia
- 2020
-
Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 59
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Fetal immune tolerance is crucial for pregnancy success. We studied the link between preeclampsia, a severe pregnancy disorder with uncertain pathogenesis, and fetal human leukocyte antigen G (HLA-G) and other genes regulating maternal immune responses.Methods: We assessed sex ratios and regulatory HLA-G haplotypes in population cohorts and series of preeclampsia and stillbirth. We studied placental mRNA expression of 136 genes by sequencing and HLA-G and interferon alpha (IFNα) protein expression by immunohistochemistry.Findings: We found underrepresentation of males in preeclamptic births, especially those delivered preterm or small for gestational age. Balancing selection at HLA-G associated with the sex ratio, stillbirth, and preeclampsia. We observed downregulation of HLA-G, its receptors, and many other tolerogenic genes, and marked upregulation of IFNA1 in preeclamptic placentas.Interpretation: These findings indicate that an evolutionary trade-off between immune tolerance and protection against infections at the maternal-fetal interface promotes genetic diversity in fetal HLA-G, thereby affecting survival, preeclampsia, and sex ratio. We highlight IFNA1 as a potential mediator of preeclampsia and a target for therapeutic trials.
|
|
