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

Pandiloski, Ninoslav LU orcid ; Horváth, Vivien LU orcid ; Karlsson, Ofelia LU orcid ; Koutounidou, Symela LU ; Dorazehi, Fereshteh LU orcid ; Christoforidou, Georgia LU ; Matas-Fuentes, Jon ; Gerdes, Patricia LU orcid ; Garza, Raquel LU orcid and Jönsson, Marie E LU , et al. (2024) In Nature Communications 15.
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... (More)

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.

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Contribution to journal
publication status
published
subject
keywords
Humans, DNA Methylation, DNA (Cytosine-5-)-Methyltransferase 1/metabolism, Neural Stem Cells/metabolism, Long Interspersed Nucleotide Elements/genetics, Epigenesis, Genetic, Promoter Regions, Genetic, Transcription Factors/metabolism, Co-Repressor Proteins/metabolism, Gene Silencing, Repressor Proteins/metabolism, Nerve Tissue Proteins
in
Nature Communications
volume
15
article number
7534
publisher
Nature Publishing Group
external identifiers
  • pmid:39214989
  • scopus:85202775829
ISSN
2041-1723
DOI
10.1038/s41467-024-50765-4
language
English
LU publication?
yes
additional info
© 2024. The Author(s).
id
6f574fb7-da12-402a-8732-75ceb3054cae
date added to LUP
2024-09-02 08:49:54
date last changed
2025-02-04 17:47:08
@article{6f574fb7-da12-402a-8732-75ceb3054cae,
  abstract     = {{<p>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.</p>}},
  author       = {{Pandiloski, Ninoslav and Horváth, Vivien and Karlsson, Ofelia and Koutounidou, Symela and Dorazehi, Fereshteh and Christoforidou, Georgia and Matas-Fuentes, Jon and Gerdes, Patricia and Garza, Raquel and Jönsson, Marie E and Adami, Anita and Atacho, Diahann A M and Johansson, Jenny G and Englund, Elisabet and Kokaia, Zaal and Jakobsson, Johan and Douse, Christopher H}},
  issn         = {{2041-1723}},
  keywords     = {{Humans; DNA Methylation; DNA (Cytosine-5-)-Methyltransferase 1/metabolism; Neural Stem Cells/metabolism; Long Interspersed Nucleotide Elements/genetics; Epigenesis, Genetic; Promoter Regions, Genetic; Transcription Factors/metabolism; Co-Repressor Proteins/metabolism; Gene Silencing; Repressor Proteins/metabolism; Nerve Tissue Proteins}},
  language     = {{eng}},
  month        = {{08}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{DNA methylation governs the sensitivity of repeats to restriction by the HUSH-MORC2 corepressor}},
  url          = {{http://dx.doi.org/10.1038/s41467-024-50765-4}},
  doi          = {{10.1038/s41467-024-50765-4}},
  volume       = {{15}},
  year         = {{2024}},
}