De novoDNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET

Abstract

SUMMARYEndogenous retroviruses (ERVs) undergo de novo DNA methylation during the first few days of mammalian embryogenesis, although the factors that control the targeting of this process are largely unknown. We asked whether KAP1 (KRAB-associated protein 1) is involved in this mechanism because of its previously defined role in maintaining the silencing of ERVs through the histone methyltransferase ESET and histone H3 lysine 9 trimethylation. Here, we demonstrate that introduced ERV sequences are sufficient to direct rapid de novo methylation of a flanked promoter in embryonic stem (ES) cells. This mechanism requires the presence of an ERV sequence-recognizing KRAB zinc-finger protein (ZFP) and both KAP1 and ESET. Furthermore, this process can also take place on a strong cellular promoter and leads to methylation signatures that are subsequently maintained in vivo throughout embryogenesis. Finally, we show that methylation of ERVs residing in the genome is affected by knockout of KAP1 in early embryos. KRAB-ZFPs, KAP1 and ESET are thus likely to be responsible for the early embryonic instatement of stable epigenetic marks at ERVcontaining loci. KEY WORDS:De novo DNA methylation, Endogenous retroviral silencing, KRAB-associated protein 1 (KAP1), TRIM28, TIF1, KRAB zincfinger protein (KRAB-ZFP), ESET (SETDB1)De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET

Evolutionally dynamic L1 regulation in embryonic stem cells

“…Cold Spring Harbor Laboratory Press on May 9, 2018 -Published by genesdev.cshlp.org Downloaded from H3K9 trimethylation, and HP1 recruitment, with DNA methylation occurring only secondarily to ensure the permanence of the silencing process (Quenneville et al 2012;Rowe et al 2013a). Our observation that KB murine L1 elements are up-regulated upon Setdb1 knockout in mES cells confirms the primary importance of histone methylation-based mechanisms in their control.…”

“…In human embryonic stem (hES) and mouse ES (mES) cells, the KRAB-ZFP-mediated docking of KAP1 at EREs triggers the formation of heterochromatin through the recruitment of the SETDB1 (also known as ESET) histone methyltransferase, responsible for trimethylating histone 3 at Lys9; histone deacetylases; and HP1 (heterochromatin protein 1), which collectively induce transcriptional repression (Schultz et al 2002;Ivanov et al 2007). The further recruitment of DNA methyltransferases (DNMTs) results in permanent silencing marks, which are subsequently maintained throughout development without need for persistent expression of sequence-specific ERErecognizing repressors (Quenneville et al 2012;Rowe et al 2013a).…”

Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential

“…4E), but such drastic decreases were not observed in OCT3/4-or SOX2-binding to LINE-1. Two proteins, KAP-1 (KRABassociated protein 1) and histone methyltransferase SET domain bifurcated 1 (ESET), have been shown to be critical in suppression of endogenous retroviruses (16). ChIP experiments revealed that in HDFs transduced with OSKM, the binding of KAP-1 to LTR7s significantly decreased in ABHD12B and HHLA1 loci, but this decrease was not observed with OSM or OSNM (OSM with NANOG instead of KLF4) (Fig.…”

Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

“…In murine ES cells, TRIM28-induced repression leads to DNA methylation, which is thought to result in permanent silencing of EREs (Quenneville et al 2012;Rowe et al 2013a). We thus examined the methylation status of EREs in human ES cells by correlating publicly available ENCODE (Encyclopedia of DNA Elements) Project DNA methylation data with our TRIM28 ChIP-seq results.…”