The KRAB zinc finger protein ZFP809 is required to initiate epigenetic silencing of endogenous retroviruses

Abstract

Retroviruses have been invading mammalian germlines for millions of years, accumulating in the form of endogenous retroviruses (ERVs) that account for nearly one-tenth of the mouse and human genomes. ERVs are epigenetically silenced during development, yet the cellular factors recognizing ERVs in a sequence-specific manner remain elusive. Here we demonstrate that ZFP809, a member of the Kr€ uppel-associated box zinc finger protein (KRAB-ZFP) family, initiates the silencing of ERVs in a sequence-specific manner via recruitment of heterochromatin-inducing complexes. ZFP809 knockout mice display highly elevated levels of ZFP809-targeted ERVs in somatic tissues. ERV reactivation is accompanied by an epigenetic shift from repressive to active histone modifications but only slight destabilization of DNA methylation. Importantly, using conditional alleles and rescue experiments, we demonstrate that ZFP809 is required to initiate ERV silencing during embryonic development but becomes largely dispensable in somatic tissues. Finally, we show that the DNA-binding specificity of ZFP809 is evolutionarily conserved in the Muroidea superfamily of rodents and predates the endogenization of retroviruses presently targeted by ZFP809 in Mus musculus. In sum, these data provide compelling evidence that ZFP809 evolved to recognize foreign DNA and establish histone modification-based epigenetic silencing of ERVs.

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).…”

“…ZFP809, a murine-specific KRAB-ZFP, was demonstrated early on to silence exogenous MLV in embryonic carcinoma cells through recognition of the provirus primer binding site-coding sequence Goff, 2007, 2009). Curiously, depletion of ZFP809 in mice leads to de-repression of MLV-related ERVs in adult tissues but not in ESCs (Wolf et al, 2015b). Although functional data on the role of individual human KRAB-ZFPs during this period are still missing, it is noteworthy that HERVH (human endogenous retrovirus H) integrants, which appear to play an important role in human ESC pluripotency, are recognized by several KRAB-ZFPs, the levels of which change as these cells switch from a naïve to a primed pluripotent state (Theunissen et al, 2016).…”

“…Despite their abundance, the functions of KRABZFPs have long remained ill-defined, although cumulated data have implicated some of them in processes as diverse as imprinting, cell differentiation, metabolic control and sexual dimorphism (reviewed by Lupo et al, 2013). This picture changed when the KRABbinding co-factor KAP1 was demonstrated to be essential for the early embryonic repression of TEs in both mouse and human, and when a few individual KRAB-ZFPs could be linked to this function as well Goff, 2007, 2009;Wolf et al, 2015b;Rowe et al, 2010Rowe et al, , 2013Jacobs et al, 2014). It was then suspected that the primary role of KRAB-ZFPs was to silence TEs, and that their evolutionary selection represented the host component of an arms race against these genetic invaders (Jacobs et al, 2014;Castro-Diaz et al, 2014;Thomas and Schneider, 2011).…”

Erase–Maintain–Establish: Natural Reprogramming of the Mammalian Epigenome

“…ZFP57 plays a conserved role in imprinting maintenance in humans and mice. Diverse ZFPs/ZFNs (mouse/human) are involved in retrovirus silencing and other physiological functions (Okumura et al 1997;Zheng et al 2000;Li et al 2008;Takahashi et al 2009;Wolf and Goff 2009;Quenneville et al 2011;Nishitsuji et al 2012Nishitsuji et al , 2015Tan et al 2013;Castro-Diaz et al 2014;Jacobs et al 2014;Wolf et al 2015b). (Messerschmidt 2012;Messerschmidt et al 2012).…”

Differential control of retrovirus silencing in embryonic cells by proteasomal regulation of the ZFP809 retroviral repressor

“…1A). Whereas most of the components of the silencing complex are expressed ubiquitously, ZFP809 is expressed specifically in embryonic cells and not in differentiated cells (13,20). ZFP809 is the key ES cellspecific component of the silencing complex.…”