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Mini-heterochromatin domains constrain the cis-regulatory impact of SVA transposons in human brain development and disease

Horváth, Vivien LU orcid ; Garza, Raquel LU orcid ; Jönsson, Marie E LU ; Johansson, Pia A LU ; Adami, Anita LU orcid ; Christoforidou, Georgia LU ; Karlsson, Ofelia LU orcid ; Castilla Vallmanya, Laura LU orcid ; Koutounidou, Symela LU and Gerdes, Patricia LU orcid , et al. (2024) In Nature Structural & Molecular Biology
Abstract

SVA (SINE (short interspersed nuclear element)-VNTR (variable number of tandem repeats)-Alu) retrotransposons remain active in humans and contribute to individual genetic variation. Polymorphic SVA alleles harbor gene regulatory potential and can cause genetic disease. However, how SVA insertions are controlled and functionally impact human disease is unknown. Here we dissect the epigenetic regulation and influence of SVAs in cellular models of X-linked dystonia parkinsonism (XDP), a neurodegenerative disorder caused by an SVA insertion at the TAF1 locus. We demonstrate that the KRAB zinc finger protein ZNF91 establishes H3K9me3 and DNA methylation over SVAs, including polymorphic alleles, in human neural progenitor cells. The resulting... (More)

SVA (SINE (short interspersed nuclear element)-VNTR (variable number of tandem repeats)-Alu) retrotransposons remain active in humans and contribute to individual genetic variation. Polymorphic SVA alleles harbor gene regulatory potential and can cause genetic disease. However, how SVA insertions are controlled and functionally impact human disease is unknown. Here we dissect the epigenetic regulation and influence of SVAs in cellular models of X-linked dystonia parkinsonism (XDP), a neurodegenerative disorder caused by an SVA insertion at the TAF1 locus. We demonstrate that the KRAB zinc finger protein ZNF91 establishes H3K9me3 and DNA methylation over SVAs, including polymorphic alleles, in human neural progenitor cells. The resulting mini-heterochromatin domains attenuate the cis-regulatory impact of SVAs. This is critical for XDP pathology; removal of local heterochromatin severely aggravates the XDP molecular phenotype, resulting in increased TAF1 intron retention and reduced expression. Our results provide unique mechanistic insights into how human polymorphic transposon insertions are recognized and how their regulatory impact is constrained by an innate epigenetic defense system.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Nature Structural & Molecular Biology
publisher
Nature Publishing Group
external identifiers
  • pmid:38834915
ISSN
1545-9985
DOI
10.1038/s41594-024-01320-8
project
Transposable elements: human-specific gene regulation in the brain
SVA-mediated chromatin re-organization in XDP
language
English
LU publication?
yes
additional info
© 2024. The Author(s).
id
a6ad8713-c557-4a3c-ad5e-b0af06028765
date added to LUP
2024-06-05 10:52:58
date last changed
2024-06-06 03:06:36
@article{a6ad8713-c557-4a3c-ad5e-b0af06028765,
  abstract     = {{<p>SVA (SINE (short interspersed nuclear element)-VNTR (variable number of tandem repeats)-Alu) retrotransposons remain active in humans and contribute to individual genetic variation. Polymorphic SVA alleles harbor gene regulatory potential and can cause genetic disease. However, how SVA insertions are controlled and functionally impact human disease is unknown. Here we dissect the epigenetic regulation and influence of SVAs in cellular models of X-linked dystonia parkinsonism (XDP), a neurodegenerative disorder caused by an SVA insertion at the TAF1 locus. We demonstrate that the KRAB zinc finger protein ZNF91 establishes H3K9me3 and DNA methylation over SVAs, including polymorphic alleles, in human neural progenitor cells. The resulting mini-heterochromatin domains attenuate the cis-regulatory impact of SVAs. This is critical for XDP pathology; removal of local heterochromatin severely aggravates the XDP molecular phenotype, resulting in increased TAF1 intron retention and reduced expression. Our results provide unique mechanistic insights into how human polymorphic transposon insertions are recognized and how their regulatory impact is constrained by an innate epigenetic defense system.</p>}},
  author       = {{Horváth, Vivien and Garza, Raquel and Jönsson, Marie E and Johansson, Pia A and Adami, Anita and Christoforidou, Georgia and Karlsson, Ofelia and Castilla Vallmanya, Laura and Koutounidou, Symela and Gerdes, Patricia and Pandiloski, Ninoslav and Douse, Christopher H and Jakobsson, Johan}},
  issn         = {{1545-9985}},
  language     = {{eng}},
  month        = {{06}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Structural & Molecular Biology}},
  title        = {{Mini-heterochromatin domains constrain the cis-regulatory impact of SVA transposons in human brain development and disease}},
  url          = {{https://lup.lub.lu.se/search/files/188379061/publication_in_nature_structural_molecular_biology.pdf}},
  doi          = {{10.1038/s41594-024-01320-8}},
  year         = {{2024}},
}