Abstract
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.
Highlights
Subsets of endogenous retroviruses (ERVs) are derepressed in mouse embryonic stem cells deficient for Setdb[1], which catalyzes histone H3 lysine 9 trimethylation (H3K9me[3])
To analyze whether the H3K9me[3] marks on ERVs are important for silencing in differentiated cell types, we performed RNA sequencing (RNA-seq) analysis on Setdb[1] conditional knockout immortalized mouse embryonic fibroblasts[3], which is a model for differentiated cells
An RNA-seq analysis of repeats in Setdb[1] conditional knockout (cKO) immortalized mouse embryonic fibroblasts (iMEFs) revealed a substantially increased expression of ERVs after Setdb[1] depletion, five elements annotated by Repbase, i.e., MMVL30-int, MuLV-int, RLTR4_Mm, RLTR4_Mm-int, and RLTR6_Mm (Fig. 1a, highlighted in red)
Summary
Subsets of endogenous retroviruses (ERVs) are derepressed in mouse embryonic stem cells (mESCs) deficient for Setdb[1], which catalyzes histone H3 lysine 9 trimethylation (H3K9me[3]). 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 Setdb[1] in ERV silencing, which provides an additional layer of epigenetic silencing through the H3K9me[3] modification. In somatic and male germ-lineage cells, which are further differentiated, DNA methylation has been proposed to be the main mechanism to silence ERVs and nonlong terminal repeat (LTR) retroelements In this context, CpG dinucleotides of retroelements are densely methylated and Dnmt[1] inactivation leads to IAP derepression in embryos or differentiated mESCs upon depletion of LIF signals[11,12]. Our data suggest that Setdb[1] plays a more general role in ERV silencing, providing an additional silencing mechanism through H3K9me[3]
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