Suv39h-Dependent H3K9me3 Marks Intact Retrotransposons and Silences LINE Elements in Mouse Embryonic Stem Cells

Bulut-Karslıoğlu, Aydan; Rosa-Velázquez, Inti A. De La; Ramírez, Fidel; Barenboim, Maxim; Onishi-Seebacher, Megumi; Arand, Julia; Galán, Carmen; Ciulli, Alessio; Engist, Bettina; Gerle, Borbala; O’Sullivan, Roderick J.; Martens, Joost H.A.; Walter, Jörn; Manke, Thomas; Lachner, Monika; Jenuwein, Thomas

doi:10.1016/j.molcel.2014.05.029

Cited by 292 publications

(319 citation statements)

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“…6B) may explain the residual levels of H3K9me3. Alternatively, other H3K9 methyltransferases, such as SUV39H1 and/or SUV39H2, could be responsible for the residual H3K9me3 present in Setdb1 knockout germ cells (Bulut-Karslioglu et al 2014). No change in expression of the remaining known H3K9 or H3K27 histone methyltransferases was observed in the Setdb1 knockout (Supplemental Fig.…”

Section: H3k9me3 and H3k27me3 Are Reduced At Ervs In Setdb1-deficientmentioning

confidence: 99%

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

et al. 2014

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Transcription of endogenous retroviruses (ERVs) is inhibited by de novo DNA methylation during gametogenesis, a process initiated after birth in oocytes and at approximately embryonic day 15.5 (E15.5) in prospermatogonia. Earlier in germline development, the genome, including most retrotransposons, is progressively demethylated. Young ERVK and ERV1 elements, however, retain 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 (chromatin immunoprecipitation [ChIP] combined with deep sequencing) method. Although these repressive histone modifications are found predominantly on distinct genomic regions in E13.5 PGCs, they concurrently mark partially methylated long terminal repeats (LTRs) and LINE1 elements. Germline-specific conditional knockout of the H3K9 methyltransferase SETDB1 yields a decrease of both marks and DNA methylation at H3K9me3-enriched retrotransposon families. Strikingly, Setdb1 knockout E13.5 PGCs show concomitant derepression of many marked ERVs, including intracisternal A particle (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 E13.5 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.

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Section: H3k9me3 and H3k27me3 Are Reduced At Ervs In Setdb1-deficientmentioning

confidence: 99%

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

et al. 2014

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“…How these different silencing systems interact and converge to ensure TE silencing is an active area of research. In pluripotent embryonic stem (ES) cells, TEs are primarily controlled by H3K9 methylation with some contribution from DNA methylation (Matsui et al 2010;Karimi et al 2011;Bulut-Karslioglu et al 2014), while in differentiating embryos and in somatic cells, DNA methylation is the main mechanism of TE repression (Walsh et al 1998;Arand et al 2012). Mammalian fetal germline ontogeny is a peculiar developmental window where DNA methylation-mediated TE control is extensively relaxed: Genomic methylation drops from 80% to 7%, which is the lowest physiological level that a mammalian cell has been reported to attain (Hajkova et al 2002;Popp et al 2010;Seisenberger et al 2012).…”

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confidence: 99%

DNA methylation restrains transposons from adopting a chromatin signature permissive for meiotic recombination

et al. 2015

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DNA methylation is essential for protecting the mammalian germline against transposons. When DNA methylation-based transposon control is defective, meiotic chromosome pairing is consistently impaired during spermatogenesis: How and why meiosis is vulnerable to transposon activity is unknown. Using two DNA methylationdeficient backgrounds, the Dnmt3L and Miwi2 mutant mice, we reveal that DNA methylation is largely dispensable for silencing transposons before meiosis onset. After this, it becomes crucial to back up to a developmentally programmed H3K9me2 loss. Massive retrotransposition does not occur following transposon derepression, but the meiotic chromatin landscape is profoundly affected. Indeed, H3K4me3 marks gained over transcriptionally active transposons correlate with formation of SPO11-dependent double-strand breaks and recruitment of the DMC1 repair enzyme in Dnmt3L −/− meiotic cells, whereas these features are normally exclusive to meiotic recombination hot spots. Here, we demonstrate that DNA methylation restrains transposons from adopting chromatin characteristics amenable to meiotic recombination, which we propose prevents the occurrence of erratic chromosomal events.

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“…An important modification for initiating repressive chromatin formation is trimethylation of histone H3 at the lysine 9 position (H3K9me3) by two major histone methyltransferases (HMTs). Suppressor Of Variegation 3-9 Homolog (SUV39H)1/2 complexes maintain this modification at constitutive heterochromatin and most long interspersed nuclear elements (LINEs), which together encompass the vast majority of H3K9me3 in chromatin (2,3). In contrast, the HMT called SET Domain, Bifurcated 1 (SETDB1 a.k.a.…”

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confidence: 99%

“…In fully differentiated cells, such as fibroblasts, DNA methylation appears to be particularly important for ERV suppression, whereas HMTs responsible for H3K9me3 are largely dispensable (3,4). In contrast, ESC and primordial germ cells rely on H3K9me3 for ERV repression, a process that is independent of CpG methylation by DNMTs (8).…”

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confidence: 99%

The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes

Collins

Kyle

Egawa

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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) vs. 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, on 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.epigenetics | histone methylation | repression | transposable elements | retroviruses R epressive chromatin is a biochemical platform for many cellular processes (1), including gene silencing during development and the suppression of potentially mutagenic repetitive elements, such as endogenous retroviruses (ERVs). The formation and maintenance of repressive chromatin rely on epigenetic modification of its DNA and nucleosome components, including hypermethylation of CpG dinucleotides by DNA methyltransferases (DNMTs). DNA methylation patterns are conserved during replication, and this modification is thought to provide the most stable form of repression (1). An important modification for initiating repressive chromatin formation is trimethylation of histone H3 at the lysine 9 position (H3K9me3) by two major histone methyltransferases (HMTs). Suppressor Of Variegation 3-9 Homolog (SUV39H)1/2 complexes maintain this modification at constitutive heterochromatin and most long interspersed nuclear elements (LINEs), which together encompass the vast majority of H3K9me3 in chromatin (2, 3). In contrast, the HMT called SET Domain, Bifurcated 1 (SETDB1 a.k.a. ESET) is targeted primarily to ERVs, which must be silenced to maintain genome and transcriptome integrity (4).Long terminal repeat (LTR)-containing ERVs represent ∼10% of human and mouse genomes (5). Although most are defunct genomic artifacts, many species contain a substantial number of active ERVs (6). In mice, ERV expression is tissue and strain specific. The intracisternal A particle (IAP) and early transposon/ Mus musculus type D (ETn/MusD) families of ERVs are expressed predominantly in early embyronic tissues. One consequence of this de-repression is the acquisition of spontaneous germ-line mutations, with IAP and ETn retrotransposition accounting for nearly 15% of these genomic alterations in mice (5). Likewise, B lymph...

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Suv39h-Dependent H3K9me3 Marks Intact Retrotransposons and Silences LINE Elements in Mouse Embryonic Stem Cells

Cited by 292 publications

References 56 publications

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

DNA methylation restrains transposons from adopting a chromatin signature permissive for meiotic recombination

The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes

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