Cellular Memory Laboratory, Cluster for Pioneering Research, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Shogoin, Sakyo, Kyoto, 606-8507, Japan.
Nat Commun. 2018 Apr 27;9(1):1683. doi: 10.1038/s41467-018-04132-9.
Subsets of endogenous retroviruses (ERVs) are derepressed in mouse embryonic stem cells (mESCs) deficient for Setdb1, which catalyzes histone H3 lysine 9 trimethylation (H3K9me3). Most of those ERVs, including IAPs, remain silent if Setdb1 is deleted in differentiated embryonic cells; however they are derepressed when deficient for Dnmt1, suggesting that Setdb1 is dispensable for ERV silencing in somatic cells. However, H3K9me3 enrichment on ERVs is maintained in differentiated cells and is mostly diminished in mouse embryonic fibroblasts (MEFs) lacking Setdb1. Here we find that distinctive sets of ERVs are reactivated in different types of Setdb1-deficient somatic cells, including the VL30-class of ERVs in MEFs, whose derepression is dependent on cell-type-specific transcription factors (TFs). These data suggest a more general role for Setdb1 in ERV silencing, which provides an additional layer of epigenetic silencing through the H3K9me3 modification.
内源性逆转录病毒（ERVs）的亚群在缺乏催化组蛋白 H3 赖氨酸 9 三甲基化（H3K9me3）的 Setdb1 的小鼠胚胎干细胞（mESCs）中被去抑制。如果在分化的胚胎细胞中删除 Setdb1，大多数 ERVs，包括 IAPs，仍然保持沉默；然而，如果缺乏 Dnmt1，它们就会被去抑制，这表明 Setdb1 在体细胞中沉默 ERV 是可有可无的。然而，在分化细胞中，ERV 上的 H3K9me3 富集得以维持，在缺乏 Setdb1 的小鼠胚胎成纤维细胞（MEFs）中则大部分减少。在这里，我们发现不同类型的 Setdb1 缺陷体细胞中重新激活了独特的 ERV 集，包括 MEFs 中的 VL30 类 ERV，其去抑制依赖于细胞类型特异性转录因子（TFs）。这些数据表明 Setdb1 在 ERV 沉默中具有更普遍的作用，通过 H3K9me3 修饰提供了额外的表观遗传沉默层。
