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SMARCAD1 ATPase activity is required to silence endogenous retroviruses in embryonic stem cells

2019; Nature Portfolio; Volume: 10; Issue: 1 Linguagem: Inglês

10.1038/s41467-019-09078-0

2041-1723

Parysatis Sachs, Dong Ding, Philipp Bergmaier, Boris Lamp, Christina Schlagheck, Florian Finkernagel, Andrea Nist, Thorsten Stiewe, Jacqueline E. Mermoud,

Advanced biosensing and bioanalysis techniques

Abstract Endogenous retroviruses (ERVs) can confer benefits to their host but present a threat to genome integrity if not regulated correctly. Here we identify the SWI/SNF-like remodeler SMARCAD1 as a key factor in the control of ERVs in embryonic stem cells. SMARCAD1 is enriched at ERV subfamilies class I and II, particularly at active intracisternal A-type particles (IAPs), where it preserves repressive histone methylation marks. Depletion of SMARCAD1 results in de-repression of IAPs and adjacent genes. Recruitment of SMARCAD1 to ERVs is dependent on KAP1, a central component of the silencing machinery. SMARCAD1 and KAP1 occupancy at ERVs is co-dependent and requires the ATPase function of SMARCAD1. Our findings uncover a role for the enzymatic activity of SMARCAD1 in cooperating with KAP1 to silence ERVs. This reveals ATP-dependent chromatin remodeling as an integral step in retrotransposon regulation in stem cells and advances our understanding of the mechanisms driving heterochromatin establishment.