Morc3 silences endogenous retroviruses by enabling Daxx-mediated histone H3.3 incorporation

Sophia Groh, Anna Viktoria Milton, Lisa Katherina Marinelli, Cara V. Sickinger, Angela Russo, Heike Bollig, Gustavo Pereira de Almeida, Andreas Schmidt, Ignasi Forné, Axel Imhof and Gunnar Schotta ()
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Sophia Groh: Ludwig-Maximilians-University (LMU) Munich
Anna Viktoria Milton: Ludwig-Maximilians-University (LMU) Munich
Lisa Katherina Marinelli: Ludwig-Maximilians-University (LMU) Munich
Cara V. Sickinger: Ludwig-Maximilians-University (LMU) Munich
Angela Russo: Ludwig-Maximilians-University (LMU) Munich
Heike Bollig: Ludwig-Maximilians-University (LMU) Munich
Gustavo Pereira de Almeida: Ludwig-Maximilians-University (LMU) Munich
Andreas Schmidt: Ludwig-Maximilians-University (LMU) Munich
Ignasi Forné: Ludwig-Maximilians-University (LMU) Munich
Axel Imhof: Ludwig-Maximilians-University (LMU) Munich
Gunnar Schotta: Ludwig-Maximilians-University (LMU) Munich

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Endogenous retroviruses (ERVs) comprise a significant portion of mammalian genomes. Although specific ERV loci feature regulatory roles for host gene expression, most ERV integrations are transcriptionally repressed by Setdb1-mediated H3K9me3 and DNA methylation. However, the protein network which regulates the deposition of these chromatin modifications is still incompletely understood. 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. Morc3 knock-out (ko) cells display de-repression, reduced H3K9me3, and increased chromatin accessibility of distinct ERV families. We find that the Morc3 ATPase cycle and Morc3 SUMOylation are important for ERV chromatin regulation. Proteomic analyses reveal that Morc3 mutant proteins fail to interact with the histone H3.3 chaperone Daxx. This interaction depends on Morc3 SUMOylation and Daxx SUMO binding. Notably, in Morc3 ko cells, we observe strongly reduced histone H3.3 on Morc3 binding sites. Thus, our data demonstrate Morc3 as a critical regulator of Daxx-mediated histone H3.3 incorporation to ERV regions.

Date: 2021
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DOI: 10.1038/s41467-021-26288-7

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