A CRISPR Knockout Screen Identifies Retroelement Silencing Factors in Embryonic Stem Cells

In mouse embryonic stem cells (mESCs), expression of provirus and endogenous retroelements is epigenetically repressed. Although many cellular factors involved in the silencing processes have been identified, the complete molecular mechanism remains elusive. In this study, we performed a genome-wide CRISPR screen to advance our understanding of retroelement silencing in mESCs. We identified more than 80 genes involved in retroelement silencing. In particular, the BAF and HUSH complex components are linked with the repression of most of the Setdb1 targets. We characterized two factors, namely Morc2a and Dres1, which have not hitherto been implicated in retroelement silencing. Although both factors are recruited to repress provirus, their roles in repression are different. Morc2a seems to function downstream repressive epigenetic modifications. Dres1 regulates repressive epigenetic modifications associated with Setdb1. Our genome-wide CRISPR screen cataloged genes of factors, which function at different levels in retroelement silencing and provides a useful resource for further molecular studies.