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Sökning: WFRF:(Wallerman Ola)

  • Resultat 1-10 av 44
  • [1]2345Nästa
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1.
  • Ali, Muhammad Akhtar, et al. (författare)
  • The transcriptional modulator <em>ZBED6</em> regulates cell cycle and growth of human colorectal cancer cells
  • ????
  • Annan publikation (övrigt vetenskapligt)abstract
    • <p>The transcription factor <em>ZBED6</em> is a repressor of <em>IGF2</em> whose action impacts development, cell proliferation and growth in placental mammals. In human colorectal cancers, <em>IGF2</em> overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of <em>ZBED6</em> in tumorigenesis, we engineered and validated somatic cell <em>ZBED6</em> knock-outs in the human colorectal cancer cell lines RKO and HCT116. Transcriptome analyses revealed enrichment of cell cycle-related processes among differentially expressed genes in both cell lines. Chromatin immunoprecipitation sequencing analyses displayed enrichment of ZBED6 binding at genes upregulated in <em>ZBED6<sup>-/-</sup></em> knockout clones. Ten differentially expressed genes were identified as putative direct gene targets and their downregulation by ZBED6 was experimentally validated. Eight of these genes were linked to the Wnt, Hippo, TGF-b, EGFR or PI3K pathways, all involved in colorectal cancer development. Ablation of ZBED6 affected the cell cycle and led to increased growth rate of <em>ZBED6<sup>-/-</sup></em> RKO cells. These observations support a role for transcriptional modulation by ZBED6 in cell cycle regulation and growth of colorectal cancers.</p>
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2.
  • Ali, Muhammad Akhtar, et al. (författare)
  • Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells
  • 2015
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424 .- 1091-6490. ; 112:25, s. 7743-7748
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.</p>
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3.
  • Ament-Velásquez, Sandra Lorena, M.Sc., 1988-, et al. (författare)
  • The evolution of the allorecognition gene repertoire in the <em>Podospora anserina</em> species complex
  • ????
  • Annan publikation (övrigt vetenskapligt)abstract
    • <p>Across the Tree of Life, self/non-self recognition is typically achieved through highly polymorphic loci under balancing selection. In fungi, vegetative conspecific recognition, or allorecognition, is defined by the compatibility interactions between loci known as <em>het</em> genes. In this study we explore the evolution of the <em>het</em> genes in the model fungus <em>Podospora anserina</em> and its closest relatives (the <em>Podospora</em> anserina species complex). First, we used chromosome-level genome assemblies to resolve their phylogenetic relationships. We found that the species in the complex are well defined but diversified recently and rapidly, leading to high degrees of conflict at deep branches of the phylogeny. Unlike typical orthologous genes from the complex, some allorecognition genes (<em>het-z</em> and <em>het-s</em>) show trans-species polymorphism, a hallmark of long-term balancing selection. By contrast, the <em>het</em> genes belonging to the HNWD<em> </em>family exhibit a high turn-over, with losses and duplications happening often. In particular, the species <em>P. pseudocomata</em> has a considerable increase of HNWD genes. Unexpectedly, we show that the HNWD paralogs have clean defined boundaries flanked by a target site duplication (TSD), implicating a DNA transposon-like mechanism in the genesis of new duplicates. Overall, our data highlights the diversity of evolutionary histories behind individual self/non-self recognition genes at short evolutionary timescales.</p>
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5.
  • Andrade, Pedro, et al. (författare)
  • Regulatory changes in pterin and carotenoid genes underlie balanced color polymorphisms in the wall lizard
  • 2019
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - National Acad Sciences. - 0027-8424. ; 116:12, s. 5633-5642
  • Tidskriftsartikel (refereegranskat)abstract
    • Reptiles use pterin and carotenoid pigments to produce yellow, orange, and red colors. These conspicuous colors serve a diversity of signaling functions, but their molecular basis remains unresolved. Here, we show that the genomes of sympatric color morphs of the European common wall lizard (Podarcis muralis), which differ in orange and yellow pigmentation and in their ecology and behavior, are virtually undifferentiated. Genetic differences are restricted to two small regulatory regions near genes associated with pterin [sepiapterin reductase (SPR)] and carotenoid [beta-carotene oxygenase 2 (BCO2)] metabolism, demonstrating that a core gene in the housekeeping pathway of pterin biosynthesis has been coopted for bright coloration in reptiles and indicating that these loci exert pleiotropic effects on other aspects of physiology. Pigmentation differences are explained by extremely divergent alleles, and haplotype analysis revealed abundant transspecific allele sharing with other lacertids exhibiting color polymorphisms. The evolution of these conspicuous color ornaments is the result of ancient genetic variation and cross-species hybridization.
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6.
  • Birney, Ewan, et al. (författare)
  • Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
  • 2007
  • Ingår i: Nature. - 1476-4687. ; 447:7146, s. 799-816
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.</p>
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7.
  • Birney, Ewan, et al. (författare)
  • Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
  • 2007
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.</p>
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8.
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9.
  • Cavalli, Marco, et al. (författare)
  • Allele specific chromatin signals, 3D interactions, and motif predictions for immune and B cell related diseases
  • 2019
  • Ingår i: Scientific Reports. - NATURE PUBLISHING GROUP. - 2045-2322 .- 2045-2322. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Several Genome Wide Association Studies (GWAS) have reported variants associated to immune diseases. However, the identified variants are rarely the drivers of the associations and the molecular mechanisms behind the genetic contributions remain poorly understood. ChIP-seq data for TFs and histone modifications provide snapshots of protein-DNA interactions allowing the identification of heterozygous SNPs showing significant allele specific signals (AS-SNPs). AS-SNPs can change a TF binding site resulting in altered gene regulation and are primary candidates to explain associations observed in GWAS and expression studies. We identified 17,293 unique AS-SNPs across 7 lymphoblastoid cell lines. In this set of cell lines we interrogated 85% of common genetic variants in the population for potential regulatory effect and we identified 237 AS-SNPs associated to immune GWAS traits and 714 to gene expression in B cells. To elucidate possible regulatory mechanisms we integrated long-range 3D interactions data to identify putative target genes and motif predictions to identify TFs whose binding may be affected by AS-SNPs yielding a collection of 173 AS-SNPs associated to gene expression and 60 to B cell related traits. We present a systems strategy to find functional gene regulatory variants, the TFs that bind differentially between alleles and novel strategies to detect the regulated genes.</p>
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10.
  • Enroth, Stefan, et al. (författare)
  • Cancer associated epigenetic transitions identified by genome-wide histone methylation binding profiles in human colorectal cancer samples and paired normal mucosa
  • 2011
  • Ingår i: BMC Cancer. - 1471-2407 .- 1471-2407. ; 11, s. 450
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Background: Despite their well-established functional roles, histone modifications have received less attention than DNA methylation in the cancer field. In order to evaluate their importance in colorectal cancer (CRC), we generated the first genome-wide histone modification profiles in paired normal colon mucosa and tumor samples. Methods: Chromatin immunoprecipitation and microarray hybridization (ChIP-chip) was used to identify promoters enriched for histone H3 trimethylated on lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in paired normal colon mucosa and tumor samples from two CRC patients and for the CRC cell line HT29. Results: By comparing histone modification patterns in normal mucosa and tumors, we found that alterations predicted to have major functional consequences were quite rare. Furthermore, when normal or tumor tissue samples were compared to HT29, high similarities were observed for H3K4me3. However, the differences found for H3K27me3, which is important in determining cellular identity, indicates that cell lines do not represent optimal tissue models. Finally, using public expression data, we uncovered previously unknown changes in CRC expression patterns. Genes positive for H3K4me3 in normal and/or tumor samples, which are typically already active in normal mucosa, became hyperactivated in tumors, while genes with H3K27me3 in normal and/or tumor samples and which are expressed at low levels in normal mucosa, became hypersilenced in tumors. Conclusions: Genome wide histone modification profiles can be used to find epigenetic aberrations in genes associated with cancer. This strategy gives further insights into the epigenetic contribution to the oncogenic process and may identify new biomarkers.</p>
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