We find that the Morc3 ATPase cycle and Morc3 SUMOylation are important for ERV chromatin regulation. Morc3 knock-out (ko) cells display de-repression, reduced H3K9me3, and increased chromatin accessibility of distinct ERV families. Here, we perform a genome-wide single guide RNA (sgRNA) screen for genes involved in ERV silencing and identify the GHKL ATPase protein Morc3 as a top-scoring hit. However, the protein network which regulates the deposition of these chromatin modifications is still incompletely understood. Although specific ERV loci feature regulatory roles for host gene expression, most ERV integrations are transcriptionally repressed by Setdb1-mediated H3K9me3 and DNA methylation. Endogenous retroviruses (ERVs) comprise a significant portion of mammalian genomes.
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