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Articles de revues sur le sujet "H3K4me1"
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O'Neill, Laura P., Hugh T. Spotswood, Milan Fernando et Bryan M. Turner. « Differential loss of histone H3 isoforms mono-, di- and tri-methylated at lysine 4 during X-inactivation in female embryonic stem cells ». Biological Chemistry 389, no 4 (1 avril 2008) : 365–70. http://dx.doi.org/10.1515/bc.2008.046.
Texte intégralRésumé :
Abstract Silencing of genes on one of the two female X chromosomes early in development helps balance expression of X-linked genes between XX females and XY males and involves chromosome-wide changes in histone variants and modifications. Mouse female embryonic stem (ES) cells have two active Xs, one of which is silenced on differentiation, and provide a powerful model for studying the dynamics of X inactivation. Here, we use immunofluorescence microscopy of metaphase chromosomes to study changes in H3 mono-, di- or tri-methylated at lysine 4 (H3K4me1, -2 or -3) on the inactivating X (Xi) in female ES cells. H3K4me3 is absent from Xi in approximately 25% of chromosome spreads by day 2 of differentiation and in 40–50% of spreads by days 4–6, making it one of the earliest detectable changes on Xi. In contrast, loss of H3K4me2 occurs 1–2 days later, when histone acetylation also diminishes. Remarkably, H3K4me1 is depleted on both (active) X chromosomes in undifferentiated female ES cells, and on the single X in males, and remains depleted on Xi. Consistent with this, chromatin immunoprecipitation reveals differentiation-related reductions in H3K4me2 and H3K4me3 at the promoter regions of genes undergoing X-inactivation in female ES cells, but no comparable change in H3K4me1.
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Guo, Qiaoyan, Xiaoxia Li, Hongbo Han, Chaoyuan Li, Shujun Liu, Wenhui Gao et Guangdong Sun. « Histone Lysine Methylation in TGF-β1 Mediated p21 Gene Expression in Rat Mesangial Cells ». BioMed Research International 2016 (2016) : 1–9. http://dx.doi.org/10.1155/2016/6927234.
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Transforming growth factor beta1- (TGF-β1-) induced p21-dependent mesangial cell (MC) hypertrophy plays a key role in the pathogenesis of chronic renal diseases including diabetic nephropathy (DN). Increasing evidence demonstrated the role of posttranscriptional modifications (PTMs) in the event; however, the precise regulatory mechanism of histone lysine methylation remains largely unknown. Here, we examined the roles of both histone H3 lysine 4 and lysine 9 methylations (H3K4me/H3K9me) in TGF-β1 induced p21 gene expression in rat mesangial cells (RMCs). Our results indicated that TGF-β1 upregulated the expression of p21 gene in RMCs, which was positively correlated with the increased chromatin marks associated with active genes (H3K4me1/H3K4me2/H3K4me3) and negatively correlated with the decreased levels of repressive marks (H3K9me2/H3K9me3) at p21 gene promoter. TGF-β1 also elevated the recruitment of the H3K4 methyltransferase (HMT) SET7/9 to the p21 gene promoter. SET7/9 gene silencing with small interfering RNAs (siRNAs) significantly abolished the TGF-β1 induced p21 gene expression. Taken together, these results reveal the key role of histone H3Kme in TGF-β1 mediated p21 gene expression in RMC, partly through HMT SET7/9 occupancy, suggesting H3Kme and SET7/9 may be potential renoprotective agents in managing chronic renal diseases.
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Lichtenberg, Jens, Elisabeth F. Heuston, Cheryl A. Keller, Ross C. Hardison et David M. Bodine. « Comparison of Expression and Epigenetic Profiles in Human and Mouse Erythropoiesis and Megakaryopoiesis Using a Systems Biology Model ». Blood 126, no 23 (3 décembre 2015) : 2383. http://dx.doi.org/10.1182/blood.v126.23.2383.2383.
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Abstract To date numerous datasets of gene expression and epigenetic profiles for mouse and human hematopoietic cells have been generated. While individual data sets for a particular cell type have been correlated, no approach exists to harness all expression and epigenetic profiles for the different types of hematopoietic cells. Our goal is to develop a systems biology platform to compare epigenetic profiles of hematopoietic cells towards a better understanding of epigenetic mechanisms governing hematopoiesis. To provide the necessary foundation to support systematic studies of hematopoiesis, we have developed the Systems Biology Repository (SBR, http://sbrblood.nhgri.nih.gov), a data "ranch" for organizing and analyzing transcriptome and epigenome data cells throughout differentiation. To populate SBR, we extracted, curated, annotated, and integrated all human and mouse hematopoietic datasets available through the Encyclopedia of DNA Elements (ENCODE), the Gene Expression Omnibus (GEO) and the Short Read Repository (SRR). These include genome-wide profiles of DNA methylation, histone methylation and acetylation, transcription factor occupancy (ChIPSeq), chromatin accessibility (DNaseISeq, ATACSeq, FAIRESeq), and coding as well as non-coding transcriptional profiles (RNASeq). To demonstrate the utility of SBR, we conducted three different analyses. The first was a vertical study of HistoneSeq (H3K4me1, H3K4me2, H3K4me3, and H3K27ac), DNA methylation and RNASeq profiles during mouse erythroid differentiation. We found a global decrease in DNA methylation from hematopoietic stem and progenitor cells (HSC) through common myeloid progenitors (CMP), erythroid progenitor cells (MEP) and erythroblasts (ERY; 92936 peaks in HSC to 14422 in ERY). The number of expressed genes (using a tags per million cutoff of 10) increased in erythroid progenitors (8901 in HSC to 10778 in CMP and 10670 in MEP) before decreasing in ERY (8654). 62% of histone marks delineating active enhancers (H3K27ac, H3K4me1) are present in both HSC and ERY, while 48% arise de novo during differentiation. In contrast, only 16% of active promoter specific histone marks (H3K4me2, H3K4me3) are present in both HSC and ERY. For a horizontal analysis we compared the DNA methylation, RNASeq, histone modification (H3K4me1, H3K4me2, H3K4me3, and H3K27ac) and transcription factor binding (GATA1 and NFE2) profiles of erythroblasts (ERY) and megakaryocytes (MEG). We found a similar relationship between gene expression and the histone and DNA methylation profiles in each cell type but differences between expression and in transcription factor occupancy. DNA methylation and H3K4me3 was enriched in the gene body of expressed genes (>36%) for both ERY (p ≤ 0.001) and MEG (p ≤ 0.01). In contrast DNA methylation was enriched in the upstream and downstream regions of non-coding RNA genes (p ≤ 0.001). Transcription factor occupancy was cell type specific: 79% of GATA1 sites are in ERY and 72% of NFE2 sites are in MEG. In erythroblasts, DNA methylation and GATA1 binding in the gene body are associated with gene silencing (4 fold difference, p ≤ 0.001), while in megakaryocytes, DNA methylation and NFE2 binding in the gene body are associated with gene activation (8 fold difference, p ≤ 0.001). We used the Mouse Genome Informatics homology map data to perform a cross-species comparison of the expression profiles of mouse and human multipotent progenitors (MPP), proerythroblasts and orthochromatic erythroblasts. We found a total of 5247 genes expressed at significantly different levels (p ≤ 0.001) between human and mouse MPP, while only 2010 genes were expressed at significantly similar levels (p ≤ 0.001). At the proerythroblast and orthochromatic erythroblast stages 7696 genes and 6571 genes were expressed at significantly different levels (p ≤ 0.001) between human and mouse respectively, while 2024 and 2560 genes were expressed at significantly similar levels (p ≤ 0.001). These data are consistent with previous studies showing differences in the transcriptional profiles of mouse and human hematopoietic cells. In summary, SBR provides a foundation to model the genetic and epigenetic landscape in both the mouse and human hematopoietic system, and enables functional correlations to be made between the species. As SBR is expanded to include data from patient cells, it will be possible to model epigenetic changes associated with disease. Disclosures No relevant conflicts of interest to declare.
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Adelman, Emmalee R., Jian Shi et Maria E. Figueroa. « Aging Human Hematopoietic Stem Cells Manifest Massive Epigenetic Reprogramming and Altered Gene Splicing of Key Hematopoietic Gene Sets ». Blood 128, no 22 (2 décembre 2016) : 885. http://dx.doi.org/10.1182/blood.v128.22.885.885.
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Abstract Aging leads to impairment of hematopoietic stem cell (HSC) function with decreased self-renewal, imbalanced differentiation potential and an increased risk to develop myeloid malignancies. These malignancies are associated with epigenetic deregulation, which contributes to pathogenesis. Notably, studies in murine models have revealed epigenetic changes in aged HSC. However, it is unknown if this occurs in normal human HSC aging and whether it may contribute to HSC dysfunction. Therefore, we performed comprehensive epigenomic and transcriptional profiling in primary human HSC (Lin-, CD34+, CD38-) isolated from young (18-30 yo), mid (45-55 yo) and old (65-75 yo) healthy donors. Using a micro-ChIP-seq protocol we profiled H3K4me1, H3K4me3, H3K27me3 and H3K27ac in 4-7 donors per age group, as well as genome-wide DNA methylation (5mC), hydroxymethylation (5hmC) and RNA-seq. Analysis of enhancer-associated marks revealed that with age there is marked reduction in both H3K4me1 and H3K27ac (20,783 and 15,625 peaks lost, respectively; log10likelihood ratio >3). Gene ontology analysis of these lost peaks revealed their association with genes involved in hematopoiesis and, RNA splicing and chromatin organization, respectively (ChIPenrich, FDR<0.05). In addition, regions depleted in H3K4me1 are enriched for PU.1, FLI1, ETS, and CTCF binding sites (Homer, q<0.00001). We next asked if aging results in specific remodeling of poised (H3K4me1>H3K4me3, H3K27ac-) and active (H3K4me1>H3K4me3, H3K27ac+) enhancers. We found age-related loss of H3K4me1 enrichment at 10,696 poised enhancers, which are associated with hematopoiesis and T- and B-cell receptor signaling (FDR<0.05). We also identified 17,242 active enhancers in young HSC, 7,057 of which are depleted in old HSC. This loss of active enhancers targets genes associated with hematopoiesis, immune signaling and myeloid malignancies (FDR<0.05). Next we analyzed the impact of aging on promoter-associated marks, H3K4me3 and H3K27me3. Remarkably, while aging leads to loss of 22,689 H3K4me3 peaks, only 1,339 H3K27me3 peaks are lost. Loss of H3K4me3 targets genes involved in inflammatory response, development and WNT signaling (FDR<0.05). Given this uneven change in H3K4me3/H3K27me3 with aging, we hypothesized this may correlate with changes in bivalently marked promoters, which regulate key developmental genes. Out of 3,947 bivalent promoters in young HSC, 842 are lost in aged HSC. This loss of bivalency affects genes involved in WNT, Cadherin and Hedgehog signaling pathways (FDR<0.05). Next we analyzed changes in cytosine modifications. We observe widespread gain of 5hmC (n=14,554 differentially hydroxymethylated regions [DHMR]; FDR <0.005), with specific enrichment at introns and exons (p<2.2e-16), as well as enrichment for GATA and KLF binding sites (Homer, q<0.00001). These DHMR target genes involved in hematopoiesis, proteins regulated by alternative splicing, and pathways associated with cancer (FDR<0.05). In contrast, much more subtle changes are found in 5mC with HSC aging, with only 529 differentially methylated regions (q-value <0.05, meth.diff >20%). However, these subtle changes also target genes associated with cadherin and WNT signaling. Finally, RNA-seq analysis revealed that this age-associated epigenetic reprogramming is accompanied by an overall trend to gene downregulation. Amongst the genes most affected are the nuclear lamin gene LMNA (mutated in progeria syndrome), splicing factors SRSF7 and U2AF1 and, the transcription factors KLF3/6 and HIF1α (FDR <0.05, fold change >1.5). Notably, changes in expression also include significant differential exon usage, which may be mediated by DHMR at intron-exon boundaries: 575 genes show altered exon usage (FDR <0.05, fold change>1.5) including LMNA and the epigenetic modifiers BRD9, CITED2, KDM6A and SETD6. In summary, we have completed the first comprehensive epigenomic profiling of aging in human HSC. Our findings show massive epigenetic remodeling in aged HSC, consisting of loss of activating histone marks primarily targeting enhancers and bivalent promoters at genes involved in hematopoiesis and developmental pathways. Cytosine modifications show widespread changes in 5hmC, targeting intron-exon boundaries. Globally, this epigenetic reprogramming results in overall gene downregulation and altered splicing of genes important for HSC regulation. Disclosures No relevant conflicts of interest to declare.
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Deshpande, Neha, Rachel Jordan, Michelle Henderson Pozzi et Mary Bryk. « Histone 3 lysine 4 monomethylation supports activation of transcription in S. cerevisiae during nutrient stress ». Current Genetics 68, no 2 (18 janvier 2022) : 181–94. http://dx.doi.org/10.1007/s00294-022-01226-2.
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AbstractMono-methylation of the fourth lysine on the N-terminal tail of histone H3 was found to support the induction of RNA polymerase II transcription in S. cerevisiae during nutrient stress. In S. cerevisiae, the mono-, di- and tri-methylation of lysine 4 on histone H3 (H3K4) is catalyzed by the protein methyltransferase, Set1. The three distinct methyl marks on H3K4 act in discrete ways to regulate transcription. Nucleosomes enriched with tri-methylated H3K4 are usually associated with active transcription whereas di-methylated H3K4 is associated with gene repression. Mono-methylated H3K4 has been shown to repress gene expression in S. cerevisiae and is detected at enhancers and promoters in eukaryotes. S. cerevisiae set1Δ mutants unable to methylate H3K4 exhibit growth defects during histidine starvation. The growth defects are rescued by either a wild-type allele of SET1 or partial-function alleles of set1, including a mutant that predominantly generates H3K4me1 and not H3K4me3. Rescue of the growth defect is associated with induction of the HIS3 gene. Growth defects observed when set1Δ cultures were starved for isoleucine and valine were also rescued by wild-type SET1 or partial-function set1 alleles. The results show that H3K4me1, in the absence of H3K4me3, supports transcription of the HIS3 gene and expression of one or more of the genes required for biosynthesis of isoleucine and valine during nutrient stress. Set1-like methyltransferases are evolutionarily conserved, and research has linked their functions to developmental gene regulation and several cancers in higher eukaryotes. Identification of mechanisms of H3K4me1-mediated activation of transcription in budding yeast will provide insight into gene regulation in all eukaryotes.
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Adelman, Emmalee, André Olsson, Tingting Qin, R. Coleman Lindsley, Rafael Bejar, Nathan Salomonis, Lee Grimes et Maria E. Figueroa. « Integrative Epigenetic and Single-Cell RNA-Seq Profiling of Human Hematopoietic Stem Cells Reveals Epigenetic Reprogramming of Enhancer and Regulatory Elements during Normal Aging ». Blood 130, Suppl_1 (7 décembre 2017) : 770. http://dx.doi.org/10.1182/blood.v130.suppl_1.770.770.
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Abstract Aging is associated with impaired hematopoietic stem cell (HSC) function, increased risk of myeloid malignancies and the acquisition of clonal hematopoiesis of indeterminate potential (CHIP). Little is known about how epigenetic regulation contributes to these age-related changes in human HSC biology. Here we report a comprehensive epigenetic and transcriptomic profiling study of human HSC aging. The HSC enriched (HSCe; Lin- CD34+ CD38-) population was purified from young (18-30 yo) and aged (65-75 yo) healthy donors and used for ChIP-Seq of H3K4me1, H3K27ac, H3K4me3, H3K27me3, DNA methylation, and bulk and single-cell (sc) RNA-seq. 5-hydroxymethylcytosine (hmC) was also profiled in the Lin- CD34+ CD38+ fraction (n=4-7 per modification, per age group). Targeted exon sequencing of 128 genes revealed only 1 out of 24 donors with any mutation (DNMT3A mutation with variant allele frequency of 0.12); thus, we concluded that any observed epigenetic or transcriptional changes with age could not be due to CHIP. Analysis of histone modifications revealed significant changes in aged HSCe compared to young, affecting 21,022 H3K4me1, 15,686 H3K4me3 and 27,071 H3K27ac peaks, with the vast majority of peaks (>98%) losing signal intensity with age (log likelihood ratio >3). In contrast, only 1,748 H3K27me3 peaks changed with age. Genes with age-related loss of H3K4me1, H3K4me3, or H3K27ac tended to lower expression in aged HSCe compared to young, while genes with reduced H3K27me3 tended to higher expression (t-test, p < 0.05). Functional annotation of regions with decreased H3K4me1 and H3K27ac showed they are associated with genes involved in hematopoiesis and chromatin organization, and RNA splicing, respectively; while sites with age-associated decrease in H3K4me3 and H3K27me3 are associated with developmental pathways (ChIP-enrich, FDR <0.05). Given these marked changes in H3K4me1 and H3K27ac, we hypothesized that enhancers may be deregulated with HSCe aging. We found that 35% (n=4,519) of all active enhancers (H3K27ac+, H3K4me1>H3K4me3, > 3 kb from TSS) lost H3K27ac with age, including enhancers regulating numerous hematopoietic transcription factors such as RUNX3, FLI1, GATA2, GFI1, HIF1A, and KLF6, as well as epigenetic modifiers BCOR, DNMT3A, DOT1 L and KMT2A, and the gene mutated in progeria syndromes, LMNA .KEGG pathway analysis of all active enhancers lost with age exhibited enrichment for B- and T-cell signaling, and leukemic and apoptosis pathways (ChIP-enrich, FDR<0.05). In addition, analysis of bivalent promoters revealed that 1,017 out of 3,967 bivalent promoters identified in young HSCe shifted from bivalency towards repression in aged HSCe, due to loss of H3K4me3. These lost bivalent promoters are enriched for WNT, Hedgehog and Cadherin signaling pathways and include several HOXC cluster genes and WNT factors (ChIP-enrich, FDR<0.05). Notably, analysis of DNA methylation showed only focal changes, with 529 differentially methylated regions with aging (q-value < 0.05 and methylation difference ≥20%), which were associated with cell adhesion, cadherins, and WNT-signaling (ChIP-enrich, FDR <0.05). In contrast, global profiling of hmC revealed 14,554 peaks gained (FDR<0.05) at regions enriched for GATA and KLF family transcription factor binding motifs (Homer, q<1.0e-4). At the expression level, 502 genes were differentially expressed with age (FDR < 0.05 and Fold change ≥ 1.5), with downregulation of LMNA, the splicing factors U2AF1 and SREK1, hematopoietic transcription factors HIF1A, BCL6 and KLF factors 3, 6, 7 and 10, and the epigenetic modifiers KDM3A, SETD6, SETD8 and SETD1A . Strikingly, analysis of sc-RNA-seq of young and aged HSCe showed that while 4 out of 208 young HSCe possessed elements of the aged HSCe gene signature, no young HSCe displayed the complete aged HSCe expression profile. In summary, integrative profiling of aged human HSCe reveals widespread epigenetic changes, targeting active enhancers of hematopoietic transcription factors and genes involved in immune function, thus implicating enhancer deregulation in aged HSC loss of function. Importantly, both mutational analysis and single cell RNA-seq suggest that these changes cannot be attributed to clonal hematopoiesis alone, but rather, are due in part to reprogramming of aged HSCs. Disclosures Lindsley: Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; MedImmune: Research Funding. Bejar: Genoptix: Consultancy, Honoraria, Patents & Royalties; AbbVie/Genetech: Honoraria, Other: Ad-hoc advisory board; Modus Outcomes: Consultancy, Honoraria; Foundation Medicine: Honoraria, Other: Ad-hoc advisory board; Otsuka/Astex: Honoraria, Other: Ad-hoc advisory board; Celgene: Consultancy, Honoraria, Other: DSMB, Steering Committee, Research Funding.
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Ingvarsdottir, Kristin, Chris Edwards, Min Gyu Lee, Jung Shin Lee, David C. Schultz, Ali Shilatifard, Ramin Shiekhattar et Shelley L. Berger. « Histone H3 K4 Demethylation during Activation and Attenuation of GAL1 Transcription in Saccharomyces cerevisiae ». Molecular and Cellular Biology 27, no 22 (17 septembre 2007) : 7856–64. http://dx.doi.org/10.1128/mcb.00801-07.
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ABSTRACT In mammalian cells, histone lysine demethylation is carried out by two classes of enzymes, the LSD1/BHC110 class and the jumonji class. The enzymes of the jumonji class in the yeast Saccharomyces cerevisiae have recently also been shown to have lysine demethylation activity. Here we report that the protein encoded by YJR119c (termed KDM5), coding for one of five predicted jumonji domain proteins in yeast, specifically demethylates trimethylated histone H3 lysine 4 (H3K4me3), H3K4me2, and H3K4me1 in vitro. We found that loss of KDM5 increased mono-, di-, and trimethylation of lysine 4 during activation of the GAL1 gene. Interestingly, cells deleted of KDM5 also displayed a delayed reduction of K4me3 upon reestablishment of GAL1 repression. These results indicate that K4 demethylation has two roles at GAL1, first to establish appropriate levels of K4 methylation during gene activation and second to remove K4 trimethylation during the attenuation phase of transcription. Thus, analysis of lysine demethylation in yeast provides new insight into the physiological roles of jumonji demethylase enzymes.
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Ngo, Vu, Zhao Chen, Kai Zhang, John W. Whitaker, Mengchi Wang et Wei Wang. « Epigenomic analysis reveals DNA motifs regulating histone modifications in human and mouse ». Proceedings of the National Academy of Sciences 116, no 9 (12 février 2019) : 3668–77. http://dx.doi.org/10.1073/pnas.1813565116.
Texte intégralRésumé :
Histones are modified by enzymes that act in a locus, cell-type, and developmental stage-specific manner. The recruitment of enzymes to chromatin is regulated at multiple levels, including interaction with sequence-specific DNA-binding factors. However, the DNA-binding specificity of the regulatory factors that orchestrate specific histone modifications has not been broadly mapped. We have analyzed 6 histone marks (H3K4me1, H3K4me3, H3K27ac, H3K27me3, K3H9me3, H3K36me3) across 121 human cell types and tissues from the NIH Roadmap Epigenomics Project as well as 8 histone marks (with addition of H3K4me2 and H3K9ac) from the mouse ENCODE Consortium. We have identified 361 and 369 DNA motifs in human and mouse, respectively, that are the most predictive of each histone mark. Interestingly, 107 human motifs are conserved between the two species. In human embryonic cell line H1, we mutated only the found DNA motifs at particular loci and the significant reduction of H3K27ac levels validated the regulatory roles of the perturbed motifs. The functionality of these motifs was also supported by the evidence that histone-associated motifs, especially H3K4me3 motifs, significantly overlap with the expression of quantitative trait loci SNPs in cancer patients more than the known and random motifs. Furthermore, we observed possible feedbacks to control chromatin dynamics as the found motifs appear in the promoters or enhancers associated with various histone modification enzymes. These results pave the way toward revealing the molecular mechanisms of epigenetic events, such as histone modification dynamics and epigenetic priming.
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Schulz, Vincent P., Kimberly Lezon-Geyda, Yelena Maksimova et Patrick G. Gallagher. « Enhancers and Super Enhancers Are Associated With Genes That Control Phenotypic Traits In Primary Human Erythroid Cells ». Blood 122, no 21 (15 novembre 2013) : 1200. http://dx.doi.org/10.1182/blood.v122.21.1200.1200.
Texte intégralRésumé :
Abstract Identification of cell-type specific enhancers is important for understanding the regulation of programs controlling cellular development and differentiation. Recent studies have shown that enhancers are frequently associated with biologically relevant and disease-associated genetic variants. We hypothesized that unique sets of enhancers and super enhancers regulate gene expression in erythroid cells, a specialized cell type evolved to carry oxygen, and associated variants influence erythroid phenotypic variability. Active enhancers are part of a chromatin landscape marked by histone H3 lysine 4 monomethylation (H3K4me1) and histone H3 lysine 27 acetylation (H3K27Ac). A subset of enhancers, called super enhancers, important for regulating genes critical for cell-type specific identify, have been described. Super enhancers span large regions of chromatin, have domains of transcription factors (TF), significant amounts of H3K4me1 and H3K27Ac modification, and significant amounts of Mediator (MED1) occupancy, frequently with the transcriptional activator BRD4. Using ChIP-seq, genome wide maps of enhancers were constructed for H3K4me1, H3K27Ac, MED1, and BRD4 using primary human erythroid cell chromatin. These data were combined with parallel gene expression analyses determined via RNA-seq and enhancers and super enhancers identified. Cell and tissue-type specific enhancers act over distances of tens to hundreds of kilobases, thus bona fide erythroid enhancers are expected to be enriched in the genomic vicinity of genes expressed and functional in erythroid cells. Sites of occupancy of H3K4me1 were correlated with levels of gene expression in erythroid cells. To exclude gene promoters, H3K4me1 within 1kb of annotated transcriptional start sites (TSS) were excluded from analyses. Consistent with their predicted function, there was significantly higher levels of erythroid transcription for genes with H3K4me1 occupancy within 1-50kb of the TSS of genes cf. genes with H3K4me1 occupancy >50kb of a TSS (p value<2.2e-16). There was also significantly higher expression of genes with H3K4me1 occupancy within 1-50kb of the TSS in erythroid cells cf. non-erythroid cells (T lymphocyte). The top over represented TF motifs at sites of H3K4me1 were GATA1, AP1/NFE2, and KLF1. To explore whether candidate erythroid enhancers are enriched in regions associated with biologically relevant erythroid cell traits, candidate enhancers were mapped to a data set of erythroid-associated SNPs from the NHGRI GWAS catalog. 32 enhancers mapped to sites previously associated with biologically relevant erythroid traits. SNPs changed TF binding motifs at numerous enhancers including GATA1 motifs in the BCL11A, TFRC and ATP24 loci, an NFE2 motif in the ATP2B4 locus, and a TAL1 motif in the BCL11A locus. Super enhancers were identified as described (Cell 153:307, 2013) by finding regions with the highest levels of clustered chromatin modification/occupancy. Super enhancers defined by H3K4me1 and H3K27Ac modifications yielded 231 regions, BRD4 occupancy yielded 166 regions, and MED1 occupancy yielded 52 regions. H3K4me1/H3K27Ac-marked SE regions were found near the FOXO3, GATA2, STAT5A, TAL1, and ZFPM1 gene loci. BRD4- and MED1-marked super enhancers were found near the critical erythroid volume regulatory gene PIEZO1. The top over represented TF motifs at super enhancer sites defined by H3K4me1 were TAL1/RUNX1, GATA1, KLF1, defined by BRD4 were TAL1, KLF1, and MYC, and defined by MED1 were GATA1, MYC and CTCF. Mapping of super enhancers to erythroid-associated SNPs from the GWAS catalog of the NHGRI revealed many super enhancers mapped to regions associated with biologically relevant erythroid cell traits. For example, super enhancers identified by H3K4me1 mapped to loci for BCL11A, TFRC, KIT, HBS1L, MYB, ANK1, HK1, and the alpha-globin gene cluster; super enhancers identified by BRD4 localized to the alpha-globin cluster and the PIEZO1 gene locus. Perturbation of enhancer function during erythroid development and differentiation may lead to dysregulation of gene expression with concomitant phenotypic consequences. Insights into regulation of programs of gene expression in obtained from study of erythroid enhancers will provide insights into the functional significance of sequence variation associated with quantitative traits and inherited and acquired hematologic disease. Disclosures: No relevant conflicts of interest to declare.
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Mantsoki, Anna, Karla Parussel et Anagha Joshi. « Identification and Characterisation of Putative Enhancer Elements in Mouse Embryonic Stem Cells ». Bioinformatics and Biology Insights 15 (janvier 2021) : 117793222097462. http://dx.doi.org/10.1177/1177932220974623.
Texte intégralRésumé :
Enhancer elements control mammalian transcription largely in a cell-type-specific manner. The genome-wide identification of enhancer elements and their activity status in a cellular context is therefore fundamental to understanding cell identity and function. We determined enhancer activity in mouse embryonic stem (ES) cells using chromatin modifications and characterised their global properties. Specifically, we first grouped enhancers into 5 groups using multiple H3K4me1, H3K27ac, and H3K27me3 modification data sets. Active enhancers (simultaneous presence of H3K4me1 and H3K27ac) were enriched for binding of pluripotency factors and were found near pluripotency-related genes. Although both H3K4me1-only and active enhancers were enriched for super-enhancers and a TATA box like motif, active enhancers were preferentially bound by RNA polII (s2) and were enriched for bidirectional transcription, while H3K4me1-only enhancers were enriched for RNA polII (8WG16) suggesting they were likely poised. Bivalent enhancers (simultaneous presence of H3K4me1 and H3K27me3) were preferentially in the vicinity of bivalent genes. They were enriched for binding of components of polycomb complex as well as Tcf3 and Oct4. Moreover, a ‘CTTTCTC’ de-novo motif was enriched at bivalent enhancers, previously identified at bivalent promoters in ES cells. Taken together, 3 histone modifications successfully demarcated active, bivalent, and poised enhancers with distinct sequence and binding features.
Thèses sur le sujet "H3K4me1"
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FASCIANI, ALESSANDRA. « Development of an in vitro disease model for dissecting the epigenetic mechanisms underlying pathogenesis of Kabuki syndrome ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2018. http://hdl.handle.net/10281/199035.
Texte intégralRésumé :
La sindrome di Kabuki (KS) è una patologia caratterizzata da anomalie congenite multiple. Sintomi tipici sono anomalie scheletriche, disabilità cognitiva lieve-moderata e difetti nello sviluppo cranio-facciale. Recentemente, i geni KMT2D e KDM6A sono stati identificati come geni causativi della malattia nel 60-80% dei casi. Questi geni codificano enzimi che modificano gli istoni e sono parte del complesso multiproteico COMPASS-like MLL4. Questo complesso è respondabile del rimodellamento della cromatina delle regioni enhancers. Uno dei maggiori ostacoli per lo studio dei meccanismi molecolari della patologia è la mancanza di modelli sperimentali, sia in vitro che in vivo. Per poter comprendere gli effetti causati dalle mutazioni sul gene KMT2D, proponiamo lo sviluppo di un modello cellulare della patologia attraverso l’utilizzo di techniche di genome editing. Abbiamo deciso di concentrarci sul gene KMT2D, responsabile della monometilazione di H3K4, perchè è stato trovato più frequentemente mutato nei pazienti Kabuki. Come modello cellulare, abbiamo utilizzato le cellule staminali mesenchimali (MSC) perchè sono i precursori di osteoblasti ed condrociti, cellule da cui derivano due dei maggiori tessuti alterati nella patologia (ossa e cartilagini). Attraverso la tecnologia CRISPR/Cas abbiamo introdotto mutazioni sul gene KMT2D. Queste mutazioni portano alla produzione di una forma tronca della proteina che manca del dominio metiltransferasico. Le cellule mutate mostrano livelli ridotti di H3K4me1, ma non di H3K4me3, confermando il ruolo di mono-metilasi di KMT2D. Analizzando il fenotipo delle cellule mesenchimali nello stato indifferenziato, abbiamo osservato solo piccole differenze presenti nelle cellule mutate rispetto alle cellule non mutate. In particolare sono presenti alterazioni nella morfologia. Infatti, le cellule mutate sono più piccole e hanno un citoscheletro di actina meno strutturato. Parallelamente, abbiamo osservato che le cellule mutate non sono in grado di completare il differenziamento condrocitario, sia in termini di morfologia ma anche in termini di produzione della matrice extracellulare. Considerando anche che le cellule staminali mesenchimali mutate hanno un’alterata espressione dei fattori di trascrizione responsabili per il differenziamento condrocitario, noi ipotiziamo che uno sbilanciamento dell’attività di KMT2D causi un’alterazione strutturale e trascrizionale nelle cellule staminali mesenchimali che, a loro volta, non sono poi in grado di differenziare completamente in condrociti. La difficoltà delle cellule mutate nel completare il differenziamento condrocitario è anche confermato dall’analisi del ciclo cellulare. Infatti, le cellule mutate non sono in grado di uscire dalla fase S del ciclo cellulare, che è un passaggio importante durante il differenziamento condrocitario. Il coinvolgimento di KMT2D nel differenziamento condrocitario e nella patologia è inoltre confermato in vivo poichè la down regolazione, mediata da morfolino, di KMT2D causa alterazioni nello sviluppo craniofacciale nel modello animale di medaka. In conclusione, abbiamo sviluppato un modello in vitro della sindrome di Kabuki il quale mostra alterazioni nelle cellule staminali mesenchimali che a loro volta non sono in grado di differenziare in condrociti, i cui tessuti che ne derivano sono alterati nella patologia. Il modello animale, inoltre, conferma questo risultato mostrandosi utile per confermare e rinforzare successivi studi. Questo modello non solo può essere utile per lo studio della patologia, ma potrebbe anche essere utilizzato per lo studio di approcci terapeutici.Kabuki Syndrome (KS) is a rare multiple malformation disease characterized by intellectual disability, short stature and peculiar facial gestalt. Recently, mutations of KMT2D and KDM6A genes have been identified as causative genes in 60 to 80% of KS cases. These two genes encode for histone modifying enzymes that are specific subunit of the COMPASS-like MLL4 complex, which has been described to possess a gene-specific function by modulating the chromatin state of enhancers. The lack of any in vitro or animal disease model for KS represents a major obstacle to understand the mechanisms by which KMT2D and KDM6A gene alterations causes the disorder. We propose the development an in vitro disease model of KS through CRISPR/Cas9 system. In particular, we focused our attention ok KMT2D, a mono methyltransferase of H3K4, because it was found mutated in the majority of Kabuki patients. We used mesenchymal stem cells (MSCs) as cellular model since they are able to differentiate into osteocyte and chondrocyte, whose derived tissues are affected in Kabuki patients. In these cells, we introduced frame shift mutations that lead to the formation of a truncated form of KMT2D protein which lose the catalytic domain. Mutated MSCs show a reduction in the H3K4me1 level, but not in H3K4me3, confirming the role of KMT2D as mono methyltransferase. Analyzing the phenotype of undifferentiated MSCs, very slight differences are present between WT and mutated cells. Mutated cells appear smaller and with a less structured actin cytoskeleton. Also, KMT2D mutations impair iMSCs differentiation through chondrocyte lineages. Indeed these cells fail in chondrocyte differentiation, in terms of morphology and in terms of synthesis of extracellular matrix. Considering also that mutated iMSCs show an altered expression of chondrogenic specific transcription factors, we hypothesize that KMT2D impairment cause an alteration in undifferentiated stem cells structure and transcriptional program that, in turn, alters the differentiation process. The altered differentiation process is also confirmed by the cell cycle analysis that reveals how mutated cells are not able to exit from cell cycle, an important step during chondrogenesis. The involvement of KMT2D in chondrocyte lineage, and also in the pathology, was also confirmed in vivo because morpholino mediated down-regulation of KMT2D results in aberration of craniofacial development of medaka animal model. In conclusion, we developed a tool that will allow us to study at the molecular level the effects of KMT2D frame-shift mutations both in the undifferentiated state of MSCs but also during the differentiation process. Moreover, our results could be reinforced and confirmed in the medaka animal model. These models could be therefore a good candidate for the study of disease pathogenesis but also for drug screening approaches.
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Belhocine, Mohamed. « Etude bioinformatique de l'épigénome au cours de la différenciation des lymphocytes T et des leucémies ». Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4095.
Texte intégralRésumé :
Des études récentes ont mis en évidence qu’au moins 70% du génome humain est transcrit et produit une myriade d’ARN non codants. Au début de ma thèse j’ai utilisé des données de RNA-Seq sens-spécifique pour identifier les transcrits divergents dans les tissus primaires de souris. J’ai utilisé aussi des données ChIP-Seq afin d’analyser leurs caractéristiques épigénétiques. Nous avons trouvé que la transcription divergente est associée de manière significative à des gènes liés à la régulation de la transcription et le développement.Dans un deuxième temps, je me suis intéressé à l'identification et la caractérisation des lncRNA chez l'homme. J’ai appliqué des approches statistiques pour quantifier leur expression et identifier ceux qui sont (dé)régulés dans un contexte normal ou leucémique Dans un troisième temps. Au cours de ma thèse, je me suis attaché à étudier le mécanisme moléculaire épigénomique ainsi qu'à développer un pipeline bioinformatique permettant d'identifier les gènes (codant ou non codant) associés à des profils H3K4me2/3 étendus. Ainsi, j’ai mis en évidences que ces profils étendus étaient directement dépendants d'un processus transcriptionelle impliquant des nouveaux mécanismes de régulation. Cette étude a donné aussi lieu à une publication dont je suis cosignataire en premier auteur. (Zacarias, Belhocine et al. Journal of Immunology 2015). Cette nouvelle approche devrait s'avérer très utile dans d'autres modèles développementaux et/ou pathologiques et peuvent être utilisé comme outil de prioritisation des candidats les plus relevant dans des approches plus globaleRecent studies indicate that at least 70% of the human genome is transcribed into a myriad of both coding and non-coding RNAs. at the beginning of my thesis I used RNA-Seq data to identify divergent transcripts in mouse primary tissues. I also used the ChIP-Seq data to analyze their epigenetic characteristics. The results demonstrated that divergent transcription was significantly associated with genes related to transcription regulation and development. In a second phase, I was interested in the LncRNAs identification and characterization during the development of human T lymphocytes and in T acute lymphoblastic leukemia (T-ALL). I applied statistical approaches to quantify their expression and identify those that are regulated in a normal or leukemic contextSubsequently, I determined the most appropriate approach to prioritize the functional role of LncRNAs. Indeed, I focused on studying the molecular epigenomic mechanism marking and developed a bioinformatics pipeline to identify genes (coding or non-coding) associated with the extended profiles of H3K4me2/3. Evidence generated through the pipeline demonstrated that these extended profiles were directly dependent on specific transcriptional process involving new regulatory mechanisms.In conclusion, this body of work has resulted in a more comprehensive approach to determining the true functional role of LncRNAs in both normal biological context and in human disease
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Salvidge, William. « The role of the histone methyl-transferase, set1, in variable gene expression and cell type proportioning in D. discoideum ». Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-the-histone-methyltransferase-set1-in-variable-gene-expression-and-cell-type-proportioning-in-d-discoideum(d3d7ea3b-7f44-4f8a-ab65-b7d36a295604).html.
Texte intégralRésumé :
During multicellular development, cells must make fate decisions that reproducibly generate the correct cell type proportions. It is remarkable that in certain developmental scenarios, seemingly identical cells in a homogenous environment can achieve this. It is thought that this is possible because cell populations exhibit reproducible cell-cell variation in gene expression. How these differences are generated has been intensely studied over the past decade, with transcriptional bursting emerging as an important factor for driving variability between cells. Furthermore, it is thought that chromatin structure around gene promoters is a key regulator of transcriptional bursting. However, key questions remain. What factors regulate chromatin structure at the molecular level? Is the activity of chromatin regulators governed by random processes or entrained by one of many hidden factors such as cell cycle positioning, cell volume, metabolism? Are the proportions of cells exhibiting different bursting patterns regulated to ensure normal cell fate choice and proportioning? To address these questions, we have investigated whether different regulators of chromatin structure affect the pre-stalk/pre-spore fate decision in the social amoebae D. discoideum. We have identified that set1, a methyl-transferase responsible for generating methylation on histone 3 at position lysine 4 (H3K4me), plays a key role in controlling the balance of cell types in multicellular development as in its absence cells become autonomously primed towards a pre-stalk fate. Single cell RNA-sequencing has revealed that genes normally regulated by this modification represent a specific class of hyper-variable genes. We find that this variability is generated by specific set1 dependent repression at these loci, as upon deletion of this enzyme we see an active recruitment of more cells to an expressing state. Our data suggest that set1 activity itself is controlled by the external source of the cell cycle. This cell cycle dependent regulation robustly ensures the correct proportions of cells within the population contain levels of set1 activity that prime 25% of cells towards the pre-stalk lineage and the other 75% to the pre-spore fate. As such we believe our study reveals a novel mechanism linking specific regulation of transcriptional bursting through the activity of set1 to cell fate propensity.
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Rhodes, Christopher. « Molecular targets of chromatin marks H3K4me3, H3K9me3 and H3K27me3 in an adult germinal niche ». Thesis, The University of Texas at San Antonio, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=1556578.
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Neural stem cells (NSCs) participate in a delicate balance between maintaining cellular identity through self-renewal and differentiating into myriad neural cell types. Understanding exactly how epigenetic mechanisms regulate this balance and the subsequent differentiation process in adult mammalian brain is an ongoing effort. We conducted a genome wide association study to elucidate the roles of genes in neural progenitors regulated by chromatin modifications. Neural progenitors of baboon SVZ were examined using ChIP-Seq (chromatin immuneprecipitation followed by deep sequencing) to determine genome wide gene targets of three histone modifications: H3K4me3, H3K9me3 and H3K27me3. Our data suggest these chromatin marks are associated with genes responsible for cellular organization and morphology, proliferation and survival, neuron development. Taken together these processes suggest histone modifications, predominantly H3K27me3, are responsible for maintenance of NSC identity. Our findings also highlight the importance of using in vivo models to study the SVZ neurogenic niche and compel examination of the H3K27me3 catalyzing enzyme EZH2. In the future, the role of EZH2 will be determined by EZH2 conditional knockout and overexpression models, using stereotaxic injections of novel Cre protein and lentiviral delivery of EZH2, respectively.
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Barman, Soumi. « Construction and Senescence Phenotype Analysis of Double Mutants Encoding H3K4me3 Methyltransferases in Arabidopsis thaliana ». Thesis, California State University, Long Beach, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10257592.
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Leaf senescence, which is the final process of leaf development, involves a complex regulation of thousands of genes to recover and recycle valuable nutrients and mobilize them to growing part of the plant for high yield of fruits and grains. A greater understanding of the complex senescence gene regulation could be helpful for higher crop yield. This study is focused on three genes (ATX1, ATX3 and ATX4) that code for H3K4me3 methyl transferases to investigate their effect on flowering transition time, and their importance during senescence by assaying total chlorophyll and protein levels, and quantifying the mRNA expression of senescence marker gene WRKY75. An additive early flowering phenotype was observed for double mutants. However, no senescence alteration was found for double mutants. An increased level of total chlorophyll was shown by single mutant atx4. Significant differences for total protein were observed in leaf 6 vs. leaf 7 for double mutants atx1atx3 and atx1atx4, suggesting a faster protein degradation rate or smaller variability (reduced confidence interval) in leaf 7 data. Due to the gene redundancy of the ten-member ATX family, knocking out two genes may not adequately affect the function of H3K4 methyltransferase activity. Therefore, phenotypic analyses of triple and quadruple mutants of senescence-expressed H3K4me3 methyltransferase coding genes may show stronger senescence phenotypes. Of importance, these data show that significantly early flowering does not dictate early leaf senescence.
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Russo, A. « DIET-SPECIFIC EPIGENETIC SIGNATURE REVEALED BY H3K4ME3 AND H3K27ME3 DATA ANALYSIS IN C57BL6 MICE ». Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/365343.
Texte intégralRésumé :
Increasing evidences demonstrate that adapting to different environmental conditions is mediated by epigenetic changes, which can participate in cellular processes. In particular, the adaptation to the different caloric intakes is of great relevance as it is crucial for the organism’s fitness. Moreover, the phenotypic remodeling induced by different diets determine the susceptibility to life-threatening diseases. For example, refined sugar, fat and meat enriched diet, typical of Western countries, is thought to be responsible for about 30-35% of cancer cases, in addition to increased incidence of type 2 diabetes and cardiovascular diseases. On the other hand, caloric restriction has been shown to be the most powerful way to prolong lifespan and reduce cancer incidence in different experimental models.
Based on the hypothesis that epigenetic changes represents the mechanistic link between diet and disease risk, the aim of this work is to investigate chromatin modifications induced by different diets in murine models to identify specific epigenetic profiles associated with fat enriched diets and caloric restriction.
For this purpose, 8 weeks old C57Bl/6 female mice were divided in three groups and fed for 10 months with 3 different diets: Standard laboratory mouse Diet, Calorie Restriction without malnutrition, High Fat Diet.
Then, livers were extracted and investigated by chromatin immunoprecipitation (anti-H3K4me3, anti-H3K27me3) and transcriptomic approach for gene expression analysis.
Despite the presence of moderate technical and biological variability, data analysis demonstrated that specific epigenetic profiles were associated to different diets. In particular, the distribution and frequency of H3K4me3 enabled the clustering of samples by diet-group.
Moreover, functional annotation of genes showing an increased signal of H3K4me3 for HF or CR respect to SD on their promoter regions, resulted in significantly enriched “Type II diabetes mellitus”, for which obesity represents a critical risk factor, and “Circadian Rhythm” pathways, whose known to affect longevity.
At mechanistic level, two DNA motifs related to the transcription and chromatin regulators ZSCAN4 and REST/NRSF were found enriched in correspondence of the regulative regions of the genes of the aforementioned pathways, suggesting these factors mediate the effects of diet on chromatin and gene expression.
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Krause, Maximilian. « The role of Histone H3 Lysine 4 trimethylation in zebrafish embryonic development ». Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-222355.
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Cells within multicellular organisms share the same genetic information, yet their shape and function can differ dramatically. This diversity of form and function is established by differential use of the genetic information. Early embryonic development describes the processes that lead to a fully differentiated embryo starting from a single fertilized cell - the zygote. Interestingly, in metazoan species this early development is governed by maternally provided factors (nutrients, RNA, protein), while the zygotic genome is transcriptionally inactive. Only at a specific developmental stage, the zygotic genome becomes transcriptionally active, and zygotic transcripts drive further embryonic development. This major change is called zygotic genome activation (ZGA). While major regulators of activation of early zygotic genes could be identified recently, the molecular mechanisms that contribute to robust global genome activation during embryonic development is not fully understood. In this study, I investigated whether the establishment of histone H3 lysine 4 trimethylation (H3K4me3) is involved in zebrafish zygotic transcription activation and early embryonic development. H3K4me3 is a chromatin modification that is implicated in transcription regulation. H3K4me3 has been shown to be enriched at Transcription Start Sites (TSS) of genes prior to their activation, and is postulated facilitate transcription activation of developmentally important genes. To interfere with H3K4me3 establishment, I generated histone methyltransferase mutants. I further inhibited H3K4me3 establishment by introduction of histones with lysine 4-to-methionine (K4-to-M) substitution, which act as dominant-negative inhibitors of H3K4me3 establishment. Upon H3K4me3 reduction, I studied the resulting effect on early transcription activation. I found that H3K4me3 is not involved in transcription activation during early zebrafish embryogenesis. Finally I analyzed possible cues in DNA sequence and chromatin environment that might favor early H3K4me3 establishment. These studies show that H3K4me3 is established during ZGA, yet it is not involved in transcription activation during early zebrafish development. Establishment of H3K4me3 might be a consequence of histone methyltransferase recruitment during a permissive chromatin state, and might be targeted to CpG-rich promoter elements that are enriched for the histone variant H2A.zJede Zelle eines multizellulären Organismus enthält dieselbe Erbinformation, und doch können Form und Funktion von Zellen untereinander sehr unterschiedlich sein. Diese Diversität wird durch unterschiedliches Auslesen - Transkribieren - der Erbinformation erreicht. Embryogenese beschreibt den Prozess, der aus einer einzelnen Zelle - der Zygote - einen multizellulären Embryo entstehen lässt. Interessanterweise laufen frühe Stadien der Embryogenese ohne Transkription der embryonalen Erbinformation ab, sondern werden durch maternal bereitgestellte Faktoren ermöglicht. Erst nach einer spezies-spezifischen Entwicklungsphase wird das Erbgut der Zygote aktiv transkribiert und ermöglicht die weitere Embryonalentwicklung. Obwohl bereits wichtige Regulatoren dieser globalen Genomaktivierung identifiziert werden konnten, sind viele molekulare Mechanismen, die zur Aktivierung des zygotischen Genoms beitragen, bisher unbekannt. In der hier vorliegenden Doktorarbeit habe ich die Rolle von Histon H3 Lysin 4 Trimethylierung (H3K4me3) während der frühen Embryogenese des Zebrafischs untersucht. H3K4me3 ist eine Chromatinmodifikation, die mit aktiver Transkription in Verbindung gebracht wird. H3K4me3 ist an Transkriptions-Start-Stellen von aktiv ausgelesenen Genen angereichert und es wird vermutet, dass diese Modifikation das Binden von Transkriptionsfaktoren und der Transkriptionsmaschinerie erleichtert. Während meiner Arbeit habe ich durch Mutation verschiedener Histon-Methyltransferasen beziehungsweise die Überexpression eines dominant-negativen Histonsubstrats versucht, die Etablierung von H3K4me3 in frühen Entwicklungsstadien des Zebrafischs zu verhindern. Anschliessend habe untersucht, welchen Effekt H3K4me3-Reduktion auf Tranksriptionsaktivität entsprechender Gene hat. Allerdings konnte ich keinen Zusammenhang zwischen H3K4me3-Reduktion und Transkriptionsaktivität beobachten. Um herauszufinden, weshalb H3K4me3 dennoch während früher Embryonalstadien etabliert wird, habe ich nachfolgend untersucht, ob möglicherweise bestimmte DNASequenzen oder Chromatin-Modifikationen zur Etablierung von H3K4me3 wahrend der Embryogenese des Zebrafischs beitragen. Aus der hier vorliegenden Arbeit lässt sich schlussfolgern, dass H3K4me3 in Tranksriptionsaktivierung während früher Embryonalstadien des Zebrafischs nicht involviert ist. Möglicherweise wird H3K4me3 in diesen Stadien in einer permissiven Chromatinumgebung etabliert, bevorzugt an Promotoren mit starker H2A.z-Anreicherung und CpG-reichen DNA-Elementen
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Crump, Nicholas T. « The role of p300/CBP in dynamic acetylation of histone H3K4me3 and immediate-early gene regulation ». Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534164.
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Mantoan, Luís Paulo Benetti. « Tolerância ao défice hídrico recorrente modulado por padrões fisiológicos, bioquímicos e epigenéticos ». Botucatu, 2019. http://hdl.handle.net/11449/181040.
Texte intégralRésumé :
Orientador: Luiz Fernando Rolim de AlmeidaResumo: Plantas que presenciam a seca podem armazenar informações sobre esta experiência, tal como uma memória ao estresse. As informações adquiridas com a memória do estresse podem ser utilizadas para aumentar a tolerância a futuros eventos de défice hídrico, porém, o crescimento das plantas pode ser limitado. O objetivo deste estudo foi investigar as respostas fisiológicas, bioquímicas e epigenéticas de Sorghum bicolor (L.) Moench durante e após o primeiro e segundo evento de défice hídrico, bem como as vantagens e desvantagens de eventos recorrentes de seca para a tolerância e crescimento. Neste estudo foram utilizados quatro tratamentos que foram: Controle, onde a irrigação foi mantida, Défice Hídrico na Fase Juvenil, onde as plantas foram submetidas a desidratação na fase juvenil seguido de reidratação, Défice Hídrico na Fase Adulta, onde a irrigação foi suspensa na fase adulta seguido de reidratação e Défice Hídrico Recorrente, onde a irrigação foi suspensa na fase juvenil e adulta seguido de reidratação. Foram avaliadas as trocas gasosas, fluorescência da clorofila a, conteúdo relativo de água na folha, densidade estomática, crescimento, enzimas atioxidativas, conteúdo de açucares totais e sacarose e ocorrência da H3K4me3 no gene Sb04g038610. Mesmo com o intervalo entre o primeiro e o segundo evento de seca, o que poderia resultar na remoção da memória do estresse formada no primeiro evento, as respostas fotossintéticas, antioxidativas, morfo-anatomicas e de estado hídrico dem... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Plants that experience drought can store information about this experience, such as a memory of stress. Information acquired with stress memory can be used to increase tolerance to future water deficit events, however, plant growth may be limited. The objective of this study was to investigate the physiological, biochemical and epigenetic responses of Sorghum bicolor (L.) Moench during and after the first and second water deficit event, as well as the advantages and disadvantages of recurrent drought events for tolerance and growth. Four treatments were used: Control, where irrigation was maintained, Water Deficit in the Juvenile Phase, where the plants were submitted to dehydration in the juvenile phase followed by rehydration, Water Deficit in the Adult Phase, where irrigation was suspended in the adult phase followed by rehydration and Recurrent Water Deficit, where irrigation was suspended in the juvenile and adult phases followed by rehydration. Gas exchanges, chlorophyll a fluorescence, relative leaf water content, stomatal density, plant growth, atioxidative enzymes, total sugar and sucrose content and the occurrence of H3K4me3 in the Sb04g038610 gene were evaluated. Even with the interval between the first and second drought events, which could result in the removal of the stress memory, the photosynthetic, antioxidative, morpho-anatomical and water status responses demonstrated that S. bicolor plants showed increased tolerance to drought during recurrent water defici... (Complete abstract click electronic access below)
Doutor
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Bogeas, Alexandra. « Méthylations de l'histone H3 et contrôle épigénétique des propriétés des cellules souches de gliomes ». Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05P620/document.
Texte intégralRésumé :
Les gliomes sont les tumeurs primitives les plus fréquentes du cerveau et restent de mauvais pronostic en raison de l’inefficacité des traitements actuels. Des cellules souches cancéreuses ont été isolées à partir de gliomes de haut grade de l’adulte. Ces cellules souches de gliomes (GSC) peuvent fournir tous les sous-types cellulaires qui composent la tumeur. De nombreuses données indiquent que la résistance aux traitements est due en grande partie aux GSC. Cibler les GSC et leurs propriétés souches constitue donc un enjeu thérapeutique important. [...] Une solution pertinente de ciblage thérapeutique est de forcer les GSC à quitter leur état souche. Dans ce cadre, mes principaux travaux ont eu pour but de caractériser les changements épigénétiques des marques d’histones qui accompagnent la répression des propriétés des GSC par un groupe de micro-ARN, miR-302-367. [...] L’étude de cette plasticité par notre équipe a abouti à l’identification de miR-302-367. Son expression forcée, à l’aide de lentivirus, bloque de façon irréversible les propriétés souches et initiatrices de tumeur des GSC. L’effet suppresseur de tumeur exercé par miR offre la possibilité d’identifier les mécanismes qui régulent le maintien ou la perte des propriétés des GSC. A l’aide d’un modèle formé par une lignée de GSC et de sa contrepartie dépourvue des propriétés souches et tumorigènes GSC-miR-302-367, je me suis attachée à caractériser les méthylations de l’histone H3, qui font parties du code d’histone associé à une transcription génique respectivement active ou réprimée. Je me suis axée sur la triméthylation de la lysine 4 (H3K4me3) et de la lysine 27 (H3K27me3), respectivement permissive et répressive de la transcription. Une analyse par ChIP-seq (Immunoprécipitation de la chromatine-séquençage) des gènes associés à ces marques a été associée à la caractérisation des transcriptomes des cellules par exon-array. Nos résultats montrent que l’expression du groupe de miR-302-367 ne modifie pas de façon globale les taux des marques H3K4me3 et H3K27me3. Par contre, des changements dans des groupes de gènes circonscrits ont pu être identifiés. La corrélation positive observée entre les marques d’histones et les taux d’expression des gènes montre une conservation du code d’histone dans les cellules cancéreuses, au moins pour les marques étudiées. L’analyse des termes GO (Gene Ontology) indique que la perte des propriétés induites par miR-302-367 s’accompagne d’un engagement de GSC dans une voie de différenciation. Les gènes portant la marque répressive dans les GSC-miR-302-367 participent notamment à des catégories fonctionnelles associées à l’expression de propriétés souches et tumorigènes. L’analyse du groupe de gènes portant une marque permissive dans les GSC et répressive dans les GSC-miR-302-367, a révélé un réseau de facteurs de transcription susceptible de participer au contrôle des propriétés souches des GSC. La répression à l’aide de siRNA d’un des membres de ce réseau, le facteur de transcription ARNT2, nous a permis de révéler son rôle dans le maintien des capacités prolifératives des GSC issues de gliomes distincts et dans l’expression du facteur de transcription Nanog, connu pour son rôle central dans le contrôle des propriétés souches des GSC. Nos résultats montrent que l’analyse des changements de marques d’histone offre donc non seulement une vue d’ensemble des différents réseaux moléculaires associés au maintien ou au contraire à la répression des propriétés des GSC, mais permet d’identifier de nouveaux acteurs. L’effet stimulateur d’ARNT2 sur la croissance cellulaire et l’expression de Nanog, dans des GSC dérivées de gliomes différents aux altérations génomiques distinctes, indique que ce facteur de transcription tient une place centrale, insoupçonnée jusqu’à présent, dans la hiérarchie des gènes qui gouvernent les propriétés des GSCGliomas, the most frequent primary brain tumors, are resistant to current therapies and the survival rate of patients is very low. Within high-grade gliomas, a cell sub-population bearing stem-like properties has been isolated. These cells, called glioma stem cell (GSC), are capable of generating all glioma cellular sub-types. Recent data indicates that resistance of these aggressive tumors to therapies is mostly due to GSCs. Thus, targeting the GSCs and their stem-like properties is imperative in order to improve current therapies. [...] Another effective solution to treat GSCs is to force them to lose their stem-like properties. In this context, the aims of my major project were to characterize the epigenetic modifications of histone marks accompanying the loss of GSC stem-like properties under the influence of a cluster of micro-RNA, miR-302-367. GSCs are endowed with an exceptional plasticity, allowing them to gain or lose their stem-like state in response to modifications in their micro-environment. Our results identified the implication of miR-302-367 in the regulation of GSC plasticity. Its stable expression using lentivirus inhibits in an irreversible manner the stem-like and tumorigenic properties of GSC. The tumor-suppressor effect of this miR offers the possibility to decipher the mechanisms responsible for the maintenance or the loss of GSC stem-like properties. Using the model of GSC and their counterparts, GSC-miR-302-367, who lost their stem-like and tumorigenic properties, my aim was to identify the methylation status of histone H3 of the histone code which is known to be associated either to an active or to a repressive gene transcription. I focused on the trimethylation of lysine 4 (H3K4me3) and lysine 27 (H3K27me3), which are associated with an activation or repression of gene transcription, respectively. We performed a ChIP-seq (Chromatin-immunoprecipitation-sequencing) analysis of the respective associated genes followed by a transcriptomic (exon-array) analysis of both cell lines. Our results show that miR-302-367 expression does not alter in a global manner the expression levels of H3K4me3 and H3K27me3. On the contrary, we were able to detect modifications in a discrete group of genes. At least for the studied marks, the positive correlation between the identified histone marks and the gene expression levels indicates that the histone code is well preserved in cancer. GO (Gene Ontology) analysis indicates that miR-302-367-induced loss of stem-like properties is accompanied with activation of the differentiation process in GSC. Genes implicated in the regulation of stem-like and tumorigenic properties were found to bear the repressive histone mark in GSC-miR-302-367. From our analysis of the group of genes bearing the active histone mark in GSC and the repressive one in GSC-miR-302-367, emerged a network of transcription factors that could possibly participate in the regulation of GSC stem-like properties. Down-regulation using siRNA of a member of this network, namely ARNT2, highlighted its role in the maintenance of the proliferative dynamic, as well as the expression of the transcription factor Nanog (a major regulator of GSC stem-like properties), in GSC derived from distinct gliomas. Our histone mark modification analysis, not only elucidated the molecular pathways implicated in the maintenance or, on the contrary, in the loss of GSC stem-like properties, but also, highlighted the implication of new actors in these processes. The activator effect of ARNT2 on GSC proliferation, as well as on the expression of Nanog, observed in GSC bearing distinct genetic alterations and derived from different glioma, indicates that this transcription factor plays a major role, not documented thus far, in the regulation of GSC stem-like properties
Chapitres de livres sur le sujet "H3K4me1"
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Marwaha, Lovleen. « Genetic Influence on Ovarian Development Plasticity In Apis mellifera (Hymenoptera : Apidae) ». Dans The Polyandrous Queen Honey Bee : Biology and Apiculture, 197–210. BENTHAM SCIENCE PUBLISHERS, 2023. http://dx.doi.org/10.2174/9789815079128112010011.
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Variant genomic expression and proteomics ultimately induce plasticity in honey bees' ovarian development. The expression of the same genomic content in female castes is influenced by; the compositional difference between royal jelly and workers jelly, queen pheromones, hormones associated with metamorphosis and environmental cues. Various concerned genetic elements with diversified transcriptomics include Kr-h1,hsp, Cut-like protein gene, Ftz-F1, anti-apoptotic buffy, Incov, oat, Apaf-1, ark, Incov2, MAPK, FoxO, mTOR, Hedgehog, TGF-β, Wnt, Hippo, Toll, Imd, H3K4me3, H3K27ac, H3K36me3, etc. The specific genetic elements are responsible for the structural and functional activation of the queen ovary. In workers, the same genetic factors act as the primary criterion for induction Programme Cell Death (PCD). This chapter attributes to enlisting concerned genetic elements which serve as an inducer for divergent ovarian development. The next chapter describes the details of PCD in workers' ovaries.
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Lucchesi, John C. « Maintenance of the active and inactive states ». Dans Epigenetics, Nuclear Organization & ; Gene Function, 80–92. Oxford University Press, 2019. http://dx.doi.org/10.1093/oso/9780198831204.003.0007.
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The maintenance of a gene in an active or inactive state is carried out by epigenetic modifications of the histones and of the DNA itself. Two major classes of complexes (PRC1 and PRC2), containing Polycomb group (PcG) proteins mediate transcriptional repression. PRC2 trimethylates histone H3 at lysine 27, a modification that attracts PRC1 leading to the ubiquitination of histone H2A. Variant PRC1 complexes can be targeted first, and mono-ubiquitinated histone H2A recruits PRC2 complexes that serve as the target for canonical PRC1 complexes. PRC2 can be targeted to sites of repression by associating with long non-coding RNAs. Trithorax group (TrxG) proteins form complexes that counteract PcG-mediated repression. Some subunits of these complexes maintain and enhance transcription by carrying out different lysine methylations (H3K4me, H3K36me and H3K79me) that are associated with active gene function; other subunits remodel chromatin by displacing and repositioning nucleosomes. Additional effects on transcription are transvections, whereby somatic pairing allows the regulatory region of one allele of a gene to influence the activity of the promoter of the allele on the homologous chromosome
Actes de conférences sur le sujet "H3K4me1"
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Berger, L., T. Kolben, S. Meister, T. M. Kolben, E. Schmoeckel, D. Mayr, S. Mahner, U. Jeschke, N. Ditsch et S. Beyer. « Expression von H3K4me3 und H3K9ac in Brustkrebs ». Dans 94. Kongress der Bayerischen Gesellschaft für Geburtshilfe und Frauenheilkunde e. V. (BGGF). Georg Thieme Verlag KG, 2020. http://dx.doi.org/10.1055/s-0040-1713965.
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Berger, L., T. Kolben, S. Meister, TM Kolben, E. Schmoeckel, D. Mayr, S. Mahner, U. Jeschke, N. Ditsch et S. Beyer. « Expression of H3K4me3 and H3K9ac in breast cancer ». Dans Kongressabstracts zur Tagung 2020 der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG). © 2020. Thieme. All rights reserved., 2020. http://dx.doi.org/10.1055/s-0040-1717839.
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Meister, S., L. Hahn, S. Beyer, C. Kuhn, M. Jegen, V. von Schönfeldt, S. Corradini et al. « Die epigenetische Modifikation durch H3K4me3 und H3K9ac ist in Präeklampsieplazenten reduziert ». Dans Kongressabstracts zur Gemeinsamen Jahrestagung der Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (OEGGG) und der Bayerischen Gesellschaft für Geburtshilfe und Frauenheilkunde e.V. (BGGF). Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0041-1730489.
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Xi, Guifa, Nitin Wadhwani, Rintaro Hashizume, Barbara Mania-Farnell, Marcelo Bento Soares, Charles D. James et Tadanori Tomita. « Abstract 2871 : Global reduction of H3K4me3 improves chemotherapeutic efficacy for pediatric ependymomas ». Dans Proceedings : AACR Annual Meeting 2019 ; March 29-April 3, 2019 ; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-2871.
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Xi, Guifa, Nitin Wadhwani, Rintaro Hashizume, Barbara Mania-Farnell, Marcelo Bento Soares, Charles D. James et Tadanori Tomita. « Abstract 2871 : Global reduction of H3K4me3 improves chemotherapeutic efficacy for pediatric ependymomas ». Dans Proceedings : AACR Annual Meeting 2019 ; March 29-April 3, 2019 ; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-2871.
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Kellner, I., S. Beyer, S. Corradini, N. Rogenhofer, TM Kolben, U. Hasbargen, A. Hester et al. « Epigenetische Modifikationen durch H3K4me3 und H3K9acan der fetomaternalen Grenzzone der Plazenta im Abortgeschehen ». Dans Kongressabstracts zur Gemeinsamen Jahrestagung der Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (OEGGG) und der Bayerischen Gesellschaft für Geburtshilfe und Frauenheilkunde e.V. (BGGF). Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0041-1730484.
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Meister, S., L. Hahn, S. Beyer, C. Paul, S. Mitter, C. Kuhn, V. von Schönfeldt et al. « Die Expression von PPARγ in der Präeklampsie reguliert die Histonmodifikationen H3K4me3 und H3K9ac ». Dans Kongressabstracts zur Gemeinsamen Jahrestagung der Österreichischen Gesellschaft für Gynäkologie und Geburtshilfe (OEGGG) und der Bayerischen Gesellschaft für Geburtshilfe und Frauenheilkunde e.V. (BGGF). Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0041-1730490.
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Wehrmann, M., T. Kolben, S. Meister, T. M. Kolben, E. Schmoeckel, D. Mayr, A. Burges et al. « Gal-8, Gal-9, H3K9ac, H3K4me3 und der Glukokortikoidrezeptor als prognostische Marker im Endometriumkarzinom ». Dans 94. Kongress der Bayerischen Gesellschaft für Geburtshilfe und Frauenheilkunde e. V. (BGGF). Georg Thieme Verlag KG, 2020. http://dx.doi.org/10.1055/s-0040-1713967.
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Qiu, Hengying. « 1714c Association between h3k4me3/bdnf and the cognitive function of workers occupationally exposed to aluminium ». Dans 32nd Triennial Congress of the International Commission on Occupational Health (ICOH), Dublin, Ireland, 29th April to 4th May 2018. BMJ Publishing Group Ltd, 2018. http://dx.doi.org/10.1136/oemed-2018-icohabstracts.827.
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Hahn, L., S. Meister, S. Beyer, M. Mannewitz, S. Corradini, U. Hasbargen, S. Mahner, U. Jeschke, T. Kolben et A. Burges. « Gal-2 führt zu einer Erhöhung von H3K4me3 und H3K9ac in Trophoblasten und in der Präeklampsie ». Dans 64. Kongress der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe e. V. Georg Thieme Verlag, 2022. http://dx.doi.org/10.1055/s-0042-1756839.
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