DNA methylation governs the sensitivity of repeats to restriction by the HUSH-MORC2 corepressor

Ninoslav Pandiloski, Vivien Horváth, Ofelia Karlsson, Symela Koutounidou, Fereshteh Dorazehi, Georgia Christoforidou, Jon Matas-Fuentes, Patricia Gerdes, Raquel Garza, Marie E. Jönsson, Anita Adami, Diahann A. M. Atacho, Jenny G. Johansson, Elisabet Englund, Zaal Kokaia, Johan Jakobsson and Christopher H. Douse ()
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Ninoslav Pandiloski: Lund University
Vivien Horváth: Lund University
Ofelia Karlsson: Lund University
Symela Koutounidou: Lund University
Fereshteh Dorazehi: Lund University
Georgia Christoforidou: Lund University
Jon Matas-Fuentes: Lund University
Patricia Gerdes: Lund University
Raquel Garza: Lund University
Marie E. Jönsson: Lund University
Anita Adami: Lund University
Diahann A. M. Atacho: Lund University
Jenny G. Johansson: Lund University
Elisabet Englund: Lund University
Zaal Kokaia: Lund University
Johan Jakobsson: Lund University
Christopher H. Douse: Lund University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The human silencing hub (HUSH) complex binds to transcripts of LINE-1 retrotransposons (L1s) and other genomic repeats, recruiting MORC2 and other effectors to remodel chromatin. How HUSH and MORC2 operate alongside DNA methylation, a central epigenetic regulator of repeat transcription, remains largely unknown. Here we interrogate this relationship in human neural progenitor cells (hNPCs), a somatic model of brain development that tolerates removal of DNA methyltransferase DNMT1. Upon loss of MORC2 or HUSH subunit TASOR in hNPCs, L1s remain silenced by robust promoter methylation. However, genome demethylation and activation of evolutionarily-young L1s attracts MORC2 binding, and simultaneous depletion of DNMT1 and MORC2 causes massive accumulation of L1 transcripts. We identify the same mechanistic hierarchy at pericentromeric α-satellites and clustered protocadherin genes, repetitive elements important for chromosome structure and neurodevelopment respectively. Our data delineate the epigenetic control of repeats in somatic cells, with implications for understanding the vital functions of HUSH-MORC2 in hypomethylated contexts throughout human development.

Date: 2024
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DOI: 10.1038/s41467-024-50765-4

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