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

Abstract

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...

Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of nonhematopoietic genes

“…2,24 Setdb1 was recently shown to contribute to the silencing of ERVs in B lymphocytes; however, the transcriptional activation of ERVs was dependent on the regulatory architecture of their long terminal repeats and the availability of corresponding B-cell-specific transcription factors such as Pax5. 25 In the present study, we found that H3K9me3 and DNA methylation were not largely altered at ERV loci and derepression of ERVs was minimal in the absence of Setdb1. These results confirm previous findings obtained in neural progenitor cells and fibroblasts 2,24 and highlight the important role of DNA methylation in the silencing of ERVs in HSPCs.…”

Retrotransposon derepression leads to activation of the unfolded protein response and apoptosis in pro-B cells

“…7G), which is in full agreement with a recent study of Setdb1 function in B cells (Collins et al, 2015). In wild-type cells, Setdb1 binds to MLV retrotransposons and establishes a repressive chromatin structure that prevents access of activating transcription factors.…”

“…There is emerging evidence that transposable elements contain transcription factor binding sites (Xie et al, 2010) and may even physiologically act as tissue-specific enhancers (Xie et al, 2013). A recent study showed that the master B cell transcription factor Pax5 may mediate forced expression of the same MLV elements that we found to be upregulated in Setdb1-deficient pro-B cells (Collins et al, 2015) (Table S3). However, additional cell type-specific transcription factors are likely to contribute to MLV transcription, as Setdb1-deficient mouse embryonic fibroblasts (Matsui et al, 2010) or myeloid cells (data not shown), which do not express Pax5, also display derepression of MLV retrotransposons.…”

KRAB zinc finger proteins

“…Second, in mature T lymphocytes, a significant fraction of TEs bound by KAP1 in human ESCs still carries the co-repressor . Third, KAP1 deletion in neuronal progenitors activates some endogenous retroelements (Fasching et al, 2015), and selected ERVs are similarly induced in murine B lymphocytes or mouse embryonic fibroblasts (MEFs) depleted for SETDB1 (Collins et al, 2015;Wolf et al, 2015b). Correspondingly, human KRAB-ZFPs display extensive and cell-specific patterns of expression in all adult tissues examined Liu et al, 2014).…”