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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE60377 | GEO | 2014/09/01

SECONDARY ACCESSION(S): PRJNA259337

REPOSITORIES: GEO

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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

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

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

2011-05-21 | GSE29413 | GEO

SETDB1 Represses Endogenous and Exogenous Retroviruses in B Lymphocytes [RNA-Seq]

Project description:Genome stability relies on epigenetic mechanisms that enforce repression of endogenous retroviruses (ERVs). Current evidence suggests that distinct chromatin-based mechanisms repress ERVs in cells of embryonic origin (histone methylation-dominant) versus more differentiated cells (DNA methylation-dominant). However, the latter aspect of this model has not been tested. Remarkably, and in contrast to the prevailing model, we find that repressive histone methylation catalyzed by the enzyme SETDB1 is critical for suppression of specific ERV families and exogenous retroviruses in committed B-lineage cells from adult mice. The profile of ERV activation in SETDB1-deficient B cells is distinct from that observed in corresponding embryonic tissues, despite the loss of repressive chromatin modifications at all ERVs. We provide evidence that, upon loss of SETDB1, ERVs are activated in a lineage-specific manner depending on the set of transcription factors available to target proviral regulatory elements. These findings have important implications for genome stability in somatic cells, as well as the interface between epigenetic repression and viral latency. Expression profiling and bisulfite PCR sequencing in Setdb1 C/C and Setdb1 D/D pro-B cells

2015-07-03 | E-GEOD-69464 | biostudies-arrayexpress

The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryo

Project description:Oocytes develop the competence for meiosis and early embryogenesis during their growth. Setdb1 is a histone H3 lysine 9 (H3K9) methyltransferase required for post-implantation development and has been implicated in the transcriptional silencing of genes and endogenous retroviral elements (ERVs). To address its role in oogenesis and pre-implantation development, we conditionally deleted Setdb1 in growing oocytes. Loss of Setdb1 expression greatly impaired meiosis. It delayed meiotic resumption, altered the dynamics of chromatin condensation, and impaired kinetochore-spindle interactions, bipolar spindle organization, and chromosome segregation in more mature oocytes. The observed phenotypes related to changes in abundance of specific transcripts in mutant oocytes. Setdb1 maternally deficient embryos arrested during pre-implantation development and showed comparable defects during cell cycle progression and in chromosome segregation. Finally, transcriptional profiling data indicate that Setdb1 down-regulates rather than silences expression of ERVK and ERVL-MaLR retrotransposons and associated chimearic transcripts during oogenesis. Our results identify Setdb1 as a novel meiotic and embryonic competence factor in meiosis and mitosis, safeguarding genome integrity at the onset of life. We performed expression profiling on pools of 16 denuded GV-oocytes isolated per mouse. We used oocytes from 4 Setdb1 f/+; Zp3-cre mice and 2 Setdb1 f/- mice as controls and oocytes from 4 Setdb1 f/-; Zp3-cre mice as mutant.

2016-06-27 | E-GEOD-82002 | biostudies-arrayexpress

Transcriptome profiling of wild type and Tet1-null primordial germ cells (PGC) by Bisulfite-seq

Project description:Purpose: To investigate the effect of Tet1 depletion on global DNA methylation, we performed whole-genome bisulfite sequencing (WGBS). Methods: Starting with as little as 1400-5251 manually micro-dissected PGCs, we used an ultra-low input method, Tn5mC-seq. Results: We generated 945 million reads for Tet1Gt/Gt PGCs and 302 million reads for wild-type PGCs. We obtained 14-16 million CpG sites per genotype at 1.76-2.66x genome coverage, which enables a comprehensive view of genome-wide DNA methylation patterns in E13.5 PGCs. PGCs are almost completely unmethylated genome-wide. Loss of Tet1 led to a subtle increase of methylation level in various genomic elements including promoters, exons, introns and repetitive elements in Tet1Gt/Gt PGCs (p<0.01). Local analysis identified 4,337 differentially methylated regions (DMRs) between Tet1-/- PGCs and wild-type cells. These DMRs are associated with 5,261 genes, among which 271 genes also exhibited differential gene expression and enriched for the cell cycle pathway (FDR=0.02). Conclusions: This result revealed that demethylation of certain set of cell cycle genes is largely abolished in the Tet1-/- PGCs. Genome-wide methylation profiles of primordial germ cells derived from the wild type (WT) and Tet1-null female embryos at E13.5 were generated by whole genome bisulfite sequencing using Illumina Hiseq.

2012-11-20 | E-GEOD-41912 | biostudies-arrayexpress

SETDB1 Represses Endogenous and Exogenous Retroviruses in B Lymphocytes [array]

2015-05-29 | GSE69378 | GEO

SETDB1 Represses Endogenous and Exogenous Retroviruses in B Lymphocytes [RNA-Seq]

2015-07-03 | GSE69464 | GEO

Role of Tet1 in genomic imprinting erasure [RRBS-PGC]

Project description:Genomic imprinting is an allele-specific gene expression system important for mammalian development and function. The molecular basis of genomic imprinting is allele-specific DNA methylation 2. While it is well known that the de novo DNA methyltransferases Dnmt3a/b are responsible for the establishment of genomic imprinting, how the methylation mark is erased during primordial germ cell (PGC) reprogramming remains a mystery. Here we report that Tet1 plays a critical role in the erasure of genomic imprinting. We show that despite their identical genotype, progenies derived from mating between Tet1-KO males and wild-type females exhibit a number of variable phenotypes including placental, fetal and postnatal growth defects, and early embryonic lethality. These defects are, at least in part, caused by the dysregulation of imprinted genes, such as Peg10 and Peg3, which exhibit aberrant hypermethylation in the paternal allele of differential methylated regions (DMRs). RNA-seq reveals extensive dysregulation of imprinted genes in the next generation due to paternal functional loss of Tet1. Genome-wide DNA methylation analysis of E13.5 PGCs and sperm derived from Tet1-KO mice reveals hypermethylation of DMRs of imprinted genes in sperm, which can be traced back to PGCs. Dynamics of methylation change in Tet1-affected sites suggested that Tet1 swipes remaining methylation including imprinted genes at late reprogramming stage. We also revealed that Tet1play a role in paternal imprinting erasure in females germline. Thus, our study establishes a critical function for Tet1 in the erasure of genomic imprinting. Genome-wide DNA methylation analysis of E13.5 PGCs from control and Tet1-KO mice

2013-12-02 | E-GEOD-49762 | biostudies-arrayexpress

Hijacking of transcriptional condensates by endogenous retroviruses

Project description:Heterochromatin plays essential roles in repressing retrotransposons, e.g. endogenous retroviruses (ERVs) during mammalian development, but the contribution of retrotransposition to lethality observed in embryonic cells deficient for heterochromatin-mediated ERV repression is poorly understood. Here we report that selective degradation of the TRIM28 heterochromatin adapter protein leads to reduced association of transcriptional condensates with loci encoding super-enhancer -driven pluripotency genes in embryonic stem cells, a collapse of the pluripotency transcriptional circuit, and a pre-lethal restriction of pluripotent lineages in mouse embryos. De-repressed ERVs recruit transcriptional condensates in the absence of TRIM28, and ERV RNA facilitates condensation of RNA Polymerase II in vitro. We propose that retrotransposons contribute to the genomic distribution of nuclear condensates, and that RNA species may facilitate “hijacking” of transcriptional condensates in various developmental and disease contexts.

2022-07-08 | PXD021895 | Pride

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