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The Histone Methyltransferase SETDB1 Represses Endogenous and Exogenous Retroviruses in B Lymphocytes

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The Histone Methyltransferase SETDB1 Represses Endogenous and Exogenous Retroviruses in B Lymphocytes The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes Patrick L. Collinsa, Katherine E. Kylea, Takeshi Egawaa, Yoichi Shinkaib, and Eugene M. Oltza,1 aDepartment of Pathology, Washington University School of Medicine, St. Louis, MO 63110; and bCellular Memory Laboratory, RIKEN, Saitama 351-0198, Japan Edited by John V. Moran, University of Michigan, Ann Arbor, MI, and accepted by the Editorial Board May 21, 2015 (received for review November 19, 2014) Genome stability relies on epigenetic mechanisms that enforce tumor viruses (MMTVs). Reintegration of these expressed viruses repression of endogenous retroviruses (ERVs). Current evidence can generate mutations with potential oncogenic consequences suggests that distinct chromatin-based mechanisms repress ERVs (7). Thus, suppression of ERVs via epigenetic mechanisms is es- in cells of embryonic origin (histone methylation dominant) vs. pecially important in adult tissues that harbor cells with a high more differentiated cells (DNA methylation dominant). However, proliferative capacity. the latter aspect of this model has not been tested. Remarkably, Recent studies suggest that the mechanisms of ERV re- and in contrast to the prevailing model, we find that repressive pression in differentiated adult tissues are distinct from those histone methylation catalyzed by the enzyme SETDB1 is critical for in embryonic stem cells (ESCs) or early lineage progenitors (3). In fully differentiated cells, such as fibroblasts, DNA methylation suppression of specific ERV families and exogenous retroviruses in appears to be particularly important for ERV suppression, committed B-lineage cells from adult mice. The profile of ERV whereas HMTs responsible for H3K9me3 are largely dispens- activation in SETDB1-deficient B cells is distinct from that observed able (3, 4). In contrast, ESC and primordial germ cells rely on in corresponding embryonic tissues, despite the loss of repressive H3K9me3 for ERV repression, a process that is independent of chromatin modifications at all ERVs. We provide evidence that, on CpG methylation by DNMTs (8). For LTR-containing ERVs, loss of SETDB1, ERVs are activated in a lineage-specific manner the repressive H3K9me3 modification is mediated by SETDB1, depending on the set of transcription factors available to target which is targeted by its interactions with KAP1 and sequence- proviral regulatory elements. These findings have important im- specific zinc finger proteins (ZFPs). Depletion of either SETDB1 plications for genome stability in somatic cells, as well as the in- or KAP1 activates expression of IAPs, ETns, and other ERV terface between epigenetic repression and viral latency. families in ESCs (4, 9). However, suppression of these ERV families is maintained in differentiated cells lacking KAP1 or epigenetics | histone methylation | repression | transposable elements | SETDB1 (9). Thus, available evidence suggests that KAP1:SETDB1 retroviruses complexes are important for initial repression of ERVs in em- bryonic cells, whereas DNA methylation is critical for their si- lencing in differentiated tissues. However, a definitive test that epressive chromatin is a biochemical platform for many ERV repression is HMT independent in any adult differentiated Rcellular processes (1), including gene silencing during devel- cell types is lacking. Here, we test this model via conditional opment and the suppression of potentially mutagenic repetitive deletion of SETDB1 in developing B lymphocytes. We find that elements, such as endogenous retroviruses (ERVs). The forma- SETDB1 functions as an epigenetic repressor of all ERVs in tion and maintenance of repressive chromatin rely on epigenetic modification of its DNA and nucleosome components, including Significance hypermethylation of CpG dinucleotides by DNA methyltransferases (DNMTs). DNA methylation patterns are conserved during rep- lication, and this modification is thought to provide the most stable Mammalian genomes are replete with silent endogenous ret- roviruses (ERVs). Inappropriate ERV activation in dividing cells is form of repression (1). An important modification for initiating particularly dangerous because it can produce oncogenic muta- repressive chromatin formation is trimethylation of histone H3 at tions via new ERV insertions. Here, we show that endogenous the lysine 9 position (H3K9me3) by two major histone methyl- and exogenous retroviruses are repressed in B lymphocytes from transferases (HMTs). Suppressor Of Variegation 3-9 Homolog adult mice by methylation of histones that package viral DNA (SUV39H)1/2 complexes maintain this modification at constitutive into repressive chromatin. These findings contrast with current GENETICS heterochromatin and most long interspersed nuclear elements models, which posit that histone methylation is dispensable for (LINEs), which together encompass the vast majority of H3K9me3 ERV repression in postembryonic tissues. We also show that ERV in chromatin (2, 3). In contrast, the HMT called SET Domain, activation upon loss of histone methylation relies on specific sets Bifurcated 1 (SETDB1 a.k.a. ESET) is targeted primarily to ERVs, of transcription factors in a given cell type. Our findings uncover which must be silenced to maintain genome and transcriptome new mechanisms of genome stability and viral repression in integrity (4). mammalian cells of adult origin. Long terminal repeat (LTR)-containing ERVs represent ∼10% of human and mouse genomes (5). Although most are defunct Author contributions: P.L.C., Y.S., and E.M.O. designed research; P.L.C., K.E.K., and T.E. genomic artifacts, many species contain a substantial number of performed research; P.L.C. and Y.S. contributed new reagents/analytic tools; P.L.C. and active ERVs (6). In mice, ERV expression is tissue and strain E.M.O. analyzed data; and P.L.C., Y.S., and E.M.O. wrote the paper. specific. The intracisternal A particle (IAP) and early transposon/ The authors declare no conflict of interest. Mus musculus type D (ETn/MusD) families of ERVs are ex- This article is a PNAS Direct Submission. J.V.M. is a guest editor invited by the pressed predominantly in early embyronic tissues. One con- Editorial Board. sequence of this de-repression is the acquisition of spontaneous Data deposition: The data reported in this paper have been deposited in the Gene Ex- germ-line mutations, with IAP and ETn retrotransposition ac- pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE69504). counting for nearly 15% of these genomic alterations in mice (5). 1To whom correspondence should be addressed. Email: eoltz@wustl.edu. Likewise, B lymphocytes from leukemia-prone strains activate This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. endogenous murine leukemia viruses (MLVs) or mouse mammary 1073/pnas.1422187112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1422187112 PNAS | July 7, 2015 | vol. 112 | no. 27 | 8367–8372 Downloaded by guest on September 25, 2021 Δ Δ these lineage-committed cells, but that transcriptional activation pro-B to pre-B transition is not rescued in Setdb1 / animals by of specific ERVs relies on the regulatory architecture of their provision of a preassembled Igh transgene, suggesting that V(D)J LTRs and the availability of corresponding transcription factors. recombination is not the primary defect (Fig. S1D). IgH protein expression facilitates pro-B-cell differentiation by providing both Results proliferative and survival signals. Indeed, previous studies have SETDB1 Is Required for B-Cell Development. An outstanding ques- implicated SETDB1 in viability programs for many cell types, tion is whether HMTs are required to maintain ERV repression either through regulation of P53 or caspases (13, 14). Although Δ/Δ in the more physiologic setting of differentiated cells from an P53 deficiency fails to rescue B-cell development in the Setdb1 adult animal. For this purpose, we selectively removed Setdb1 in background (Fig. S1D), suppression of caspase pathways, via the B-lymphocyte lineage, which offers a well-defined develop- expression of the anti-apoptotic BCL2 protein, restores pro-B mental pathway characterized in great molecular detail. and pre-B-cell compartments, but not those corresponding to Genetic ablation of Setdb1 (Δ/Δ) was achieved by crossing later stages of B-cell development in the bone marrow and mice harboring published conditional alleles (Setdb1 C/C) (4) spleen (Fig. 1A and Fig. S1D). Thus, SETDB1 is essential for with an Mb1-Cre driver (10), which efficiently deletes floxed exons B-cell development beginning at its earliest stages, likely pro- and abrogates SETDB1 protein expression at the earliest stages of viding a prosurvival function. B-cell development (pro-B cells; Fig. S1 A and B). Consistent with Cellular and Molecular Defects in B Lymphocytes Lacking SETDB1. prior findings (4), SETDB1 depletion only modestly reduces Δ/Δ global H3K9me3 levels (Fig. S1B). Despite these modest meth- The rescue of Setdb1 B-cell precursors by BCL2 allowed us ylation defects, SETDB1 deficiency significantly impacts the pro- to examine the molecular and cellular pathways under SETDB1 B-cell compartment and nearly abolishes bone marrow and splenic control. Consistent with the inability of an Igh transgene to rescue the pro-B to pre-B transition, rearrangement of the endogenous B-cell populations corresponding to later stages of development Δ/Δ (Fig. 1A and Fig. S1 C and D). Prior studies,
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