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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Protracted NP95 binding to hemimethylated DNA disrupts SETDB1-mediated proviral silencing [RNA-seq]

ABSTRACT: Genetic ablation of the maintenance methyltransferase Dnmt1 induces widespread demethylation and transcriptional activation of CpG-rich IAP (intracisternal A particle) proviruses. Here, we report that this phenomenon is not simply a consequence of loss of DNA methylation. By exploiting conditional deletions of Dnmt1 and Np95, each of which is essential for maintenance methylation, we find that while IAPs are indeed de-repressed in Dnmt1-ablated embryos and embryonic stem cells (ESCs), these proviruses remain silenced in Np95-ablated cells, despite similar kinetics of passive demethylation. Paradoxically, transient IAP activation in Dnmt1-ablated ESCs requires the presence of NP95. We subsequently show that in the absence of NP95, the H3K9 methyltransferase SETDB1 maintains IAP silencing; while in the absence of DNMT1, prolonged binding of NP95 to hemimethylated DNA perturbs SETDB1-dependent H3K9me3 deposition. Taken together, these observations reveal that following acute loss of Dnmt1, H3K9 methylation-dependent IAP silencing is disrupted by aberrant NP95 binding to hemimethylated DNA. RNA-seq for Np95, Dnmt1 and Setdb1 wt, single conditional KO (cKO) and double cKO ES cells; RRBS-seq for Dnmt1 and Np95 single and double cKO ESCs; Myc-tagged NP95, DNMT1 ChIP-seq; and wt and Np95wt and cKO H3K9me3 ChIP-seq.

ORGANISM(S): Mus musculus

SUBMITTER: Takaho Endo

PROVIDER: E-GEOD-77778 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Protracted NP95 binding to hemimethylated DNA disrupts SETDB1-mediated proviral silencing [RNA-seq]

Project description:Genetic ablation of the maintenance methyltransferase Dnmt1 induces widespread demethylation and transcriptional activation of CpG-rich IAP (intracisternal A particle) proviruses. Here, we report that this phenomenon is not simply a consequence of loss of DNA methylation. By exploiting conditional deletions of Dnmt1 and Np95, each of which is essential for maintenance methylation, we find that while IAPs are indeed de-repressed in Dnmt1-ablated embryos and embryonic stem cells (ESCs), these proviruses remain silenced in Np95-ablated cells, despite similar kinetics of passive demethylation. Paradoxically, transient IAP activation in Dnmt1-ablated ESCs requires the presence of NP95. We subsequently show that in the absence of NP95, the H3K9 methyltransferase SETDB1 maintains IAP silencing; while in the absence of DNMT1, prolonged binding of NP95 to hemimethylated DNA perturbs SETDB1-dependent H3K9me3 deposition. Taken together, these observations reveal that following acute loss of Dnmt1, H3K9 methylation-dependent IAP silencing is disrupted by aberrant NP95 binding to hemimethylated DNA.

2016-04-06 | GSE77778 | GEO

Protracted NP95 binding to hemimethylated DNA disrupts SETDB1-mediated proviral silencing [RRBS-seq]

2016-05-08 | GSE77780 | GEO

Protracted NP95 binding to hemimethylated DNA disrupts SETDB1-mediated proviral silencing [ChIP-seq]

2016-05-08 | GSE77779 | GEO

Rescue of Tet2 KO ES cells in primed or naïve state

Project description:Endogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation also playing an important role. It has been suggested that SETDB1 protects ERVs from TET-dependent DNA demethylation, but the relevance of this mechanism for ERV expression remains unclear. Moreover, previous studies have been performed in primed ESCs, which are not epigenetically or transcriptionally representative of preimplantation embryos. We used naïve ESCs to investigate the role of SETDB1 in ERV regulation and, in particular, its relationship with TET-mediated DNA demethylation. Naïve ESCs show an increased dependency on SETDB1 for ERV silencing when compared to primed ESCs, including at the highly mutagenic intracisternal A particles (IAPs). We found that, in the absence of SETDB1, TET2 activates IAP elements in a catalytic-dependent manner. Surprisingly, however, TET2 does not drive changes in DNA methylation levels at IAPs, suggesting that it regulates these transposons indirectly.

2017-09-25 | GSE100863 | GEO

SETDB1 depletion in primed or naïve ES cells

2017-09-25 | GSE94444 | GEO

Histone methyltransferase SETDB1 selectively regulates cortical HTR3A interneuron development and anxiety-like behavior in mice [ChIP-seq]

Project description:SETDB1 functioning as a histone H3K9 specific methyltransferase, is critically involved in brain development. Here, we used H3K9me3 and H3K27me3 ChIPseq to study H3K9me3 redistribution and defined enhancer function of elements in genomes of NPCs from ganglionic eminences (GE) in brain-specific Setdb1 conditional knockout mice (Setdb1-Nestin-cKO) and controls at E15.5.

2023-05-18 | GSE200726 | GEO

DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements and chimaeric transcripts in mouse ES cells

Project description:DNA methylation and histone H3 lysine 9 trimethylation (H3K9me3) play important roles in silencing of genes and retroelements. However, a comprehensive comparison of genes and repetitive elements repressed by these pathways has not been reported. Here we show that in mouse embryonic stem cells (mESCs), the genes up-regulated following deletion of the H3K9 methyltransferase Setdb1 are distinct from those de-repressed in mESC deficient in the DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b, with the exception of a small number of primarily germline-specific genes. Numerous endogenous retroviruses (ERVs) lose H3K9me3 and are concomitantly de-repressed exclusively in SETDB1 knockout mESCs. Strikingly, ~15% of up-regulated genes are induced in association with de-repression of promoter proximal ERVs, half in the context of "chimaeric" transcripts that initiate within these retroelements and splice to genic exons. Thus, SETDB1 plays a previously unappreciated yet critical role in inhibiting aberrant gene transcription by suppressing the expression of proximal ERVs. NChIP-seq and mRNA-seq of WT, SETDB1 KO and DMNT1 TKO mESCs

2011-05-21 | E-GEOD-29413 | biostudies-arrayexpress

Setdb1 is required for persistence of H3K9me3 and repression of endogenous retroviruses in mouse primordial germ cells

Project description:Transcription of endogenous retroviruses (ERVs) is inhibited by de novo DNA methylation during gametogenesis, a process initiated after birth in oocytes and at ~E15.5 in prospermatogonia. Earlier in germline development however, the genome, including most retrotransposons, is progressively demethylated, with young ERVK and ERV1 elements retaining intermediate methylation levels. As DNA methylation reaches a low point in E13.5 primordial germ cells (PGCs) of both sexes, we determined whether retrotransposons are marked by H3K9me3 and H3K27me3 using a recently developed low input ChIP-seq method. Although these repressive histone modifications are predominantly found on distinct genomic regions in E13.5 PGCs, they concurrently mark partially methylated LTRs and LINE1 elements. Germline-specific conditional knock-out (KO) of the H3K9 methyltransferase SETDB1 yields a decrease of both histone marks and DNA methylation at H3K9me3 enriched retrotransposon families. Strikingly, Setdb1-KO E13.5 PGCs show concomitant de-repression of many marked ERVs, including IAP, ETn and ERVK10C elements and ERV-proximal genes, a subset in a sex-dependent manner. Furthermore, Setdb1 deficiency is associated with a reduced number of male PGCs and postnatal hypogonadism in both sexes. Taken together, these observations reveal that SETDB1 is an essential guardian against proviral expression prior to the onset of de novo DNA methylation in the germline. H3K9me3, H3K27me3 and expression profiles in Setdb1 WT, Het and KO male and female E13.5 PGCs.

2014-09-01 | E-GEOD-60377 | biostudies-arrayexpress

H3K9me3 chIP-seq 5 days following disruption of the SETDB1 H3K9 trimethylase with two different sgRNAs (6, and 9) or non-targeting control

Project description:We performed H3K9me3 chIP-seq 5 days following disruption of the SETDB1 H3K9 trimethylase with two different sgRNAs (6, and 9) or non-targeting control. Our data suggests that H3K9me3 is modestly reduced over transposable elements and some ZNF genes following disruption of SETDB1.

2017-09-06 | GSE103408 | GEO

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

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