During evolution, most ERV integrations in mammals were highly mutated or partially deleted and are thus unable to generate functional retroviral particles. Thus, our data demonstrate Morc3 as a critical regulator of Daxx-mediated histone H3.3 incorporation to ERV regions.Įndogenous retroviruses compose a significant portion of mammalian genomes. Notably, in Morc3 ko cells, we observe strongly reduced histone H3.3 on Morc3 binding sites. This interaction depends on Morc3 SUMOylation and Daxx SUMO binding. Proteomic analyses reveal that Morc3 mutant proteins fail to interact with the histone H3.3 chaperone Daxx. 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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