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Genome-wide maps of chromatin state in wild-type and SetDB1 induced knockout mESCs

ABSTRACT: We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells and characterized genome-wide SetDB1 binding and H3K9 trimethylation (H3K9me3) profiles in mouse ES cells and uncovered two distinct classes of SetDB1 binding sites, termed solo and ensemble peaks. The solo peaks were devoid of H3K9me3 and enriched near developmental regulators while the ensemble peaks were associated with H3K9me3. A subset of the SetDB1 solo peaks, particularly those near neural development related genes, was found to be associated with Polycomb Repressive Complex 2 (PRC2) as well as PRC2-interacting proteins Jarid2 and Mtf2. Genetic deletion of Setdb1 dramatically reduced Ezh2 binding as well as histone 3 lysine 27 (H3K27) trimethylation level at SetDB1 solo peaks and facilitated neural differentiation. Furthermore, we found that H3K27me3 inhibits SetDB1 methyltransferase activity in vitro. The currently identified reciprocal action between SetDB1 and PRC2 reveals a novel mechanism underlying ES cell pluripotency and differentiation regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE62666 | GEO | 2015/06/25

SECONDARY ACCESSION(S): PRJNA264743

REPOSITORIES: GEO

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Genome-wide maps of chromatin state in wild-type and SetDB1 induced knockout mESCs

Project description:We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells and characterized genome-wide SetDB1 binding and H3K9 trimethylation (H3K9me3) profiles in mouse ES cells and uncovered two distinct classes of SetDB1 binding sites, termed solo and ensemble peaks. The solo peaks were devoid of H3K9me3 and enriched near developmental regulators while the ensemble peaks were associated with H3K9me3. A subset of the SetDB1 solo peaks, particularly those near neural development related genes, was found to be associated with Polycomb Repressive Complex 2 (PRC2) as well as PRC2-interacting proteins Jarid2 and Mtf2. Genetic deletion of Setdb1 dramatically reduced Ezh2 binding as well as histone 3 lysine 27 (H3K27) trimethylation level at SetDB1 solo peaks and facilitated neural differentiation. Furthermore, we found that H3K27me3 inhibits SetDB1 methyltransferase activity in vitro. The currently identified reciprocal action between SetDB1 and PRC2 reveals a novel mechanism underlying ES cell pluripotency and differentiation regulation. Examination of 2 different histone modifications in 2 cell status.

2015-06-25 | E-GEOD-62666 | biostudies-arrayexpress

Gemone-wide maps of PRC2 complex components and chromatin states in prostate cancer cell lines

Project description:We report the high-throughput profiling of PRC2 core subunits chromatin states and histone modifications in two prostate cancer cell lines, androgen-dependent cells LNCaP and androgen-independent cells LNCaP-abl (abl). By obtaining over 1 billion bases of sequence from chromatin immunoprecipitated DNA, we generated the genome-wide localizations of EZH2, SUZ12 and H3K27 trimethylation in both cell lines, and found that EZH2 can be localized to a subsets of chromating sites that don't have H3K27me3 or SUZ12 signals nearby. Interestingly, these sites are enriched for the active histone marks H3K4 di/trimethylation as well as the RNA polymerase II, which suggest the potential function of these peaks in gene activation. Indeed, these sites are enriched near the transcription start sites of EZH2-activated genes. Further analysis of the transcription factor motifs enriched at these peaks revealed the enrichement of androgen receptor motif, suggesting a co-activator role for EZH2 in concert with AR. Our work demonstrated a novel funtion of EZH2 in transcriptional activation by directly binding to the chromatin sites that cooperate with AR. Study of the chromatin localizations of PRC2 complex core subunits and different histone marks in 2 cell types

2012-11-30 | E-GEOD-39459 | biostudies-arrayexpress

SetDB1 Contributes to Repression of Genes Encoding Developmental Regulators and Maintenance of ES Cell State

Project description:Transcription factors that play key roles in regulating embryonic stem (ES) cell state have been identified, but the chromatin regulators that help maintain ES cells are less well understood. A high-throughput shRNA screen was used to identify novel chromatin regulators that influence ES cell state. Loss of histone H3K9 methyltransferases, particularly SetDB1, had the most profound effects on ES cells. ChIP-Seq and functional analysis revealed that SetDB1 and histone H3K9 methylated nucleosomes occupy and repress genes encoding developmental regulators. These SetDB1-occupied genes are a subset of the M-bM-^@M-^\bivalentM-bM-^@M-^] genes, which contain nucleosomes with H3K4me3 and H3K27me3 modifications catalyzed by trithorax and polycomb group proteins, respectively. These genes are subjected to repression by both polycomb group proteins and SetDB1, and loss of either regulator can destabilize ES cell state. ChIP-seq data for SetDB1 and H3K9me3 in mouse ES cells.

2009-11-01 | E-GEOD-18371 | biostudies-arrayexpress

Comparison non-targeting hRNA hESCs versus UBE2K shRNA hESCs

Project description:Histones modulate gene expression by chromatin compaction, regulating numerous processes such as differentiation. However, the mechanisms underlying histone degradation remain elusive. When compared with their differentiated counterparts, immortal human embryonic stem cells (hESCs) have a unique chromatin architecture and low levels of trimethylated histone H3 at lysine 9 (H3K9me3), a heterochromatin-associated modification. Here we assess a link between the intrinsic epigenetic landscape and ubiquitin-proteasome system of hESCs. We find that hESCs exhibit high expression of UBE2K, a ubiquitin-conjugating enzyme. Loss of UBE2K increases the levels of H3K9 trimethyltransferase SETDB1, resulting in H3K9 trimethylation and repression of neurogenic genes during differentiation. Concomitantly, loss of UBE2K impairs the ability of hESCs to differentiate into neural progenitors with neurogenic properties. Besides H3K9 trimethylation, we find that UBE2K binds histone H3 to induce its polyubiquitination and degradation by the proteasome. Notably, ubc-20, the worm orthologue of UBE2K, also regulates both histone H3 levels and H3K9 trimethylation in C. elegans germline. Thus, our results indicate that UBE2K crosses evolutionary boundaries to promote histone H3 degradation and reduce H3K9me3 repressive marks in immortal cells.

2020-06-01 | PXD018625 | Pride

Identification of ubiquitination sites of purified histone H3

2020-06-01 | PXD018621 | Pride

Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations [ChIP-seq]

Project description:We find that HTT binds ATF7IP, a regulator of the histone H3 methyltransferase SETDB1. HTT inhibits the interaction of the ATF7IP-SETDB1 complex with other heterochromatin regulators and transcriptional repressors, maintaining low levels of H3K9 trimethylation (H3K9me3) in hESCs. Conversely, loss of HTT promotes global increased H3K9me3 levels. To test whether HTT knockdown also induces enrichment of H3K9me3 marks at specific genes, we performed chromatin immunoprecipitation (ChIP)-sequencing assays of hESCs using an antibody to H3K9me3.

2018-09-04 | GSE118324 | GEO

Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations [RNA-seq]

2018-09-04 | GSE118088 | GEO

Cell-type differential targeting of Setdb1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions

Project description:SETDB1 is a histone methyltransferase with essential roles in mouse development. It mediates transcriptional repression of genes and repetitive elements in different cell-types by depositing histone H3 lysine 9 trimethylation (H3K9me3). However, the function of differential H3K9me3 enrichment between cell- and tissue-types remains unclear. In this study, we demonstrate a global mutual exclusivity of H3K9me3 and CTCF across mouse tissues from different developmental time points. To investigate the mechanistic relationship, we analyzed SETDB1 depleted mouse embryonic stem cells and discovered that H3K9me3 prevents aberrant CTCF binding independently of DNA methylation and H3K9me2. Such sites are enriched with retrotransposons such as SINE B2 elements, which are not previously defined as targets of SETDB1. While the epigenetic modifier is known to silence transcriptional enhancers, its effects on higher-order chromatin structures have not been clearly defined. Overall, large chromatin structures including topologically associated domains and subnuclear compartments, remain intact. However, chromatin loops and local interactions are disrupted. Such perturbations lead to transcriptional changes by altering pre-existing chromatin landscapes, where specific genes have differential interactions with dysregulated cis-regulatory elements. This mode of transcriptional regulation is distinct from the direct repression of genic promoters or enhancers. Collectively, we find that cell-type specific targets of SETDB1 contributes to maintaining cellular identities through shaping genome architecture and transcriptomic networks by modulating CTCF binding, representing a novel function for SETDB1 and H3K9me3.

2023-11-01 | GSE184471 | GEO

A somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing [ChIP-Seq]

Project description:Subsets of endogenous retroviruses (ERVs) are derepressed in mouse embryonic stem cells (mESCs) deficient for Setdb1, which catalyzes histone H3 lysine 9 trimethylation (H3K9me3). Most of those ERVs, including IAPs, remain silent if Setdb1 is deleted in differentiated embryonic cells; however they are derepressed when deficient for Dnmt1, suggesting that Setdb1 is dispensable for ERV silencing in somatic cells. However, H3K9me3 enrichment on ERVs is maintained in differentiated cells and is mostly diminished in mouse embryonic fibroblasts (MEFs) lacking Setdb1. We find that distinctive sets of ERVs are reactivated in different types of Setdb1-deficient somatic cells, including the VL30-class of ERVs in MEFs, whose derepression is dependent on cell type-specific transcription factors (TFs). These data suggest a more general role for Setdb1 in ERV silencing, which provides an additional layer of epigenetic silencing through the H3K9me3 modification.

2018-04-02 | GSE102487 | GEO

A somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing [RNA-Seq]

2018-04-02 | GSE102486 | GEO

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