Widespread chromatin accessibility at repetitive elements links embryonic stem cells with human cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE75172 | GEO | 2016/11/01
SECONDARY ACCESSION(S): PRJNA302676
REPOSITORIES: GEO
Similar Datasets
Project description:This project aims to study human repetitive elements on human chromosome 21 (HsChr21) in a heterologous mouse environment (Tc1 mouse). The in vivo, HsChr21-wide enrichment of active histone modified regions (H3K4me3) and transcription factor binding sites was profiled by ChIP-seq in Human and Tc1 mouse tissue in order to determine the unbiased regulation of the human genome.
2013-03-21 | E-MTAB-1104 | biostudies-arrayexpress
Project description:Widespread chromatin accessibility at repetitive elements links embryonic stem cells with human cancer
| PRJNA302676 | ENA
Project description:DNA double strand breaks (DSBs) in repetitive sequences are a potent source of genomic instability, due to the possibility of non-allelic homologous recombination (NAHR). Repetitive sequences are especially at risk during meiosis, when numerous programmed DSBs are introduced into the genome to initiate meiotic recombination 1. Within the budding yeast repetitive ribosomal (r)DNA array, meiotic DSB formation is prevented in part through Sir2-dependent heterochromatin 2,3. Here, we demonstrate that the edges of the rDNA array are exceptionally susceptible to meiotic DSBs, revealing an inherent heterogeneity within the rDNA array. We find that this localised DSB susceptibility necessitates a border-specific protection system consisting of the meiotic ATPase Pch2 and the origin recognition complex subunit Orc1. Upon disruption of these factors, DSB formation and recombination specifically increased in the outermost rDNA repeats, leading to NAHR and rDNA instability. Strikingly, the Sir2-dependent heterochromatin of the rDNA itself was responsible for the induction of DSBs at the rDNA borders in pch2? cells. Thus, while Sir2 activity globally prevents meiotic DSBs within the rDNA, it creates a highly permissive environment for DSB formation at the heterochromatin/euchromatin junctions. Heterochromatinised repetitive DNA arrays are abundantly present in most eukaryotic genomes. Our data define the borders of such chromatin domains as distinct high-risk regions for meiotic NAHR, whose protection may be a universal requirement to prevent meiotic genome rearrangements associated with genomic diseases and birth defects. This SuperSeries is composed of the following subset Series: GSE30071: ssDNA mapping in dmc1 strains GSE30072: ChIP-chip of DSB factors in wild type and pch2 strains Two types of study were undertaken to understand the regulation of meiotic DSB formation close to repetitive DNA elements in yeast. First, DSBs were mapped using ssDNA enrichment in strains isogenic for a dmc1 mutation, and also including pch2 delete, orc1-161, rdna delete and a reciprocal translocation between chromosomes 2 and 12 (trans2to12). Second, the association of the DSB factors Hop1, Rec114, Mer2, and Mre1, as well as total histone H3 and H3K4-trimethylation were measured by ChIP-chip analysis in wild-type and pch2 delete strains.
2011-08-14 | E-GEOD-30073 | biostudies-arrayexpress
Project description:Cell fate transitions involve integration of genomic information encoded by regulatory elements, such as enhancers, with the cellular environment. However, identification of the genomic sequences that control the earliest steps of human embryonic development represents a formidable challenge. Here we show that in human embryonic stem cells (hESCs) unique chromatin signatures identify two distinct classes of genomic elements, both of which are marked by the presence of chromatin regulators p300 and BRG1, and monomethylation of histone H3 at lysine 4 (H3K4me1). In addition, the elements of the first class are distinguished by the acetylation of histone H3 at lysine 27 (H3K27ac), overlap with previously characterized enhancers active in hESCs, and are generally located proximally to genes expressed in hESCs and in the epiblast. In contrast, the elements within the second class, which we termed M-bM-^@M-^\poised enhancersM-bM-^@M-^], are distinguished by the absence of H3K27ac, enrichment of histone H3 lysine 27 trimethylation (H3K27me3) and are linked to genes inactive in hESCs and involved in orchestrating early steps in mammalian development, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCs to neuroepithelium, a neuroectoderm-specific subset of these elements acquires a chromatin signature associated with active enhancers. Remarkably, when assayed in zebrafish embryos, human poised enhancer elements are able to direct cell type and stage specific expression patterns characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome. Our data demonstrate that enhancers are epigenetically pre-marked and suggest a heretofore unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the unique chromatin signature associated with poised enhancers allowed us to uncover over 2,000 putative developmental regulatory sequences, thereby creating an invaluable resource for future studies and isolation of transient, rare cell populations representing early steps of human development. For GSM602289-90: RNA-seq experiments in human ESC and neuroectodermal (NEC) speheres For GSM602291-303: Genome-wide analysis of p300, H3K4me3, H3K4me1, H3K27me3 and H3K27ac in human embryonic stem cells (ESC) and neuroectoderm cells (NEC). Additionally, in H9 ESC ChIP-seq were alsoe obtained for BRG1 and FAIRE-seq was also performed.
2010-12-15 | E-GEOD-24447 | biostudies-arrayexpress
Project description:Eukaryotic cells use numerous mechanisms to ensure that no segment of their DNA is re-replicated within a single cell cycle. Despite longstanding speculation that such tight regulation is needed to protect cells from genomic alterations, this notion has never been experimentally tested. Here we show that even just transient and limited re-replication in Saccharomyces cerevisiae can strongly induce the critical first step of gene amplification, increasing gene copy number from one to two or more. The amplified units, or amplicons, consist of large internal chromosomal segments that are bounded by Ty repetitive elements and are intrachromosomally arrayed at their endogenous locus in direct head-to-tail orientation. The presence of hybrid Ty elements at inter-amplicon junctions together with the dependence of amplification on RAD52 indicate that in budding yeast these re-replication-induced gene amplifications (RRIGA) are mediated by homologous recombination between re-replicated non-allelic repetitive elements. These results finally establish the importance of stringent replication control for genome stability and suggest that re-replication should now be considered as a possible contributor to gene copy number changes in fields as diverse as cancer biology, evolution, and human genetics. The arrays in this series are primary comparative genomic hybridizations to determine genomic changes after re-replication or other genomic stresses. Genomic DNA was purified from reference Saccharomyces cerevisiae cells or survivors of re-replication or other genomic stresses, differentially labeled with Cy3 and Cy5, and competitively hybridized to a spotted microarray containing ORF and intergenic PCR products. Cy5/Cy3 ratios are normalized so that the average ratio of all elements was 1. A small number of the arrays were used to determine the extent and location of re-replication under different conditions. For those, genomic DNA was purified from non-replicating and re-replicating cells and treated as above. Series contains a total of 203 hybridizations.
2011-05-17 | E-GEOD-22018 | biostudies-arrayexpress
Project description:We have used repetitive elements, including retrotransposons, as model loci to address how and when heterochromatin forms during development. High throughput RNA-sequencing using a Nano-CAGE protocol throughout early embryogenesis revealed that the expression of repetitive elements is abundant in embryonic cells, highly dynamic and stage-specific, with most repetitive elements becoming repressed before implantation. Furthermore, we show that Line L1 elements and IAP retrotransposons become reactivated from both parental genomes in mouse embryos after fertilisation, indicating an open chromatin configuration at the beginning of development. Our data show that the reprogramming process that follows fertilisation is accompanied by a robust transcriptional activation of retrotransposons and suggests that expression of repetitive elements is initially regulated through an RNA-dependent mechanism in mammals. Genome Wide profiling of CAGE transcripts using Nano-CAGE and RNAseq in oocytes and 3 different stages of mouse pre-implantation development
2013-01-27 | E-GEOD-39849 | biostudies-arrayexpress
Project description:Germline small RNA pathways initiate silencing of repetitive elements in animals and an interplay of nuclear small RNAs and chromatin modifications maintain this silencing, protecting the germline from spreading of transposable elements. In C. elegans germline, nuclear argonaute protein HRDE-1 initiates the transcriptional silencing pathway that is crucial for long term and heritable silencing of genes and repetitive regions. Here, we show that HRDE-1 interacts with components of the splicing machinery and the exon-junction complex. One such factor is the conserved RNA helicase EMB-4/AQR that binds introns and recruits the exon-junction proteins to newly spliced RNA. Our data shows that EMB-4/AQR is required for the transcriptional silencing pathway initiated by HRDE-1 and it functions by removing the intronic barriers to silencing thorugh its helicase function.
2017-06-30 | PXD004416 | Pride
Project description:Many repetitive DNA elements are packaged in heterochromatin, but depend on occasional transcription to maintain long-term silencing. The factors that promote transcription of repeat elements in heterochromatin are largely unknown. Here, we show that DOT1L, a histone methyltransferase that modifies lysine 79 of histone H3 (H3K79), is required for transcription of major satellite repeats to maintain pericentromeric heterochromatin (PCH), and that this function is essential for preimplantation development. DOT1L is a transcriptional activator at single-copy genes but does not have a known role in repeat element transcription. We show that H3K79me3 is specifically enriched at repetitive elements, that loss of DOT1L compromises pericentromeric major satellite transcription, and that this function depends on interaction between DOT1L and the chromatin remodeler SMARCA5. DOT1L inhibition causes chromosome breaks and cell cycle defects, and leads to embryonic lethality. Together, our findings uncover a vital new role for DOT1L in transcriptional activation of heterochromatic repeats.
2023-05-26 | PXD028824 | Pride
Project description:Eukaryotic cells use numerous mechanisms to ensure that no segment of their DNA is re-replicated within a single cell cycle. Despite longstanding speculation that such tight regulation is needed to protect cells from genomic alterations, this notion has never been experimentally tested. Here we show that even just transient and limited re-replication in Saccharomyces cerevisiae can strongly induce the critical first step of gene amplification, increasing gene copy number from one to two or more. The amplified units, or amplicons, consist of large internal chromosomal segments that are bounded by Ty repetitive elements and are intrachromosomally arrayed at their endogenous locus in direct head-to-tail orientation. The presence of hybrid Ty elements at inter-amplicon junctions together with the dependence of amplification on RAD52 indicate that in budding yeast these re-replication-induced gene amplifications (RRIGA) are mediated by homologous recombination between re-replicated non-allelic repetitive elements. These results finally establish the importance of stringent replication control for genome stability and suggest that re-replication should now be considered as a possible contributor to gene copy number changes in fields as diverse as cancer biology, evolution, and human genetics.
2011-05-17 | GSE22018 | GEO
Project description:Bivalent chromatin domains consisting of the activating histone 3 lysine 4 trimethylation (H3K4me3) and repressive histone 3 lysine 27 trimethylation (H3K27me3) histone modifications are enriched at developmental genes that are repressed in embryonic stem cells but active during differentiation. However, it is unknown whether another repressive histone modification, histone 4 lysine 20 trimethylation (H4K20me3), co-localizes with activating histone marks in ES cells. Here, we describe the previously uncharacterized coupling of the repressive H4K20me3 heterochromatin mark with the activating histone modifications H3K4me3 and histone 3 lysine 36 trimethylation (H3K36me3), and transcriptional machinery (RNA polymerase II; RNAPII), in ES cells. These newly described bivalent domains consisting of H3K4me3/H4K20me3 are predominantly located in intergenic regions and near transcriptional start sites of active genes, while H3K36me3/H4K20me3 are located in intergenic regions and within gene body regions of active genes. Global sequential ChIP, also termed reChIP-Seq, confirmed the simultaneous presence of H3K4me3 and H4K20me3 at the same genomic regions in ES cells. Genes containing H3K4me3/H4K20me3 exhibit decreased RNAPII pausing and are poised for deactivation of RNAPII binding during differentiation relative to H3K4me3 marked genes. An evaluation of transcription factor (TF) binding motif enrichment revealed that DNA sequence may play a role in shaping the landscape of these novel bivalent domains. Moreover, H3K4me3/H4K20me3 and H3K36me3/H4K20me3 bound regions are enriched with repetitive LINE and LTR elements.
2018-06-18 | GSE115907 | GEO