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Loss of SETDB1-mediated H3K9me3 in human neural progenitor cells leads to transcriptional activation of L1 retrotransposons

Karlsson, Ofelia LU orcid ; Pandiloski, Ninoslav LU orcid ; Horvath, Vivien LU orcid ; Adami, Anita LU orcid ; Garza, Raquel LU orcid ; Johansson, Pia A. LU ; Johansson, Jenny G. LU ; Douse, Christopher H. LU orcid and Jakobsson, Johan LU orcid (2026) In Nucleic Acids Research 54(4).
Abstract

Heterochromatin is characterized by an inaccessibility to the transcriptional machinery and is associated with the histone mark H3K9me3. However, studying the functional consequences of heterochromatin loss in human cells has been challenging. Here, we used CRISPRi-mediated silencing of the histone methyltransferase SETDB1 to remove H3K9me3 heterochromatin in human neural progenitor cells. Despite a major loss of H3K9me3 peaks resulting in genome-wide reorganization of heterochromatin domains, silencing of SETDB1 had a limited effect on cell viability. Cells remained proliferative and expressed appropriate marker genes. We found that a key event following the loss of SETDB1-mediated H3K9me3 was the expression of evolutionarily young L1... (More)

Heterochromatin is characterized by an inaccessibility to the transcriptional machinery and is associated with the histone mark H3K9me3. However, studying the functional consequences of heterochromatin loss in human cells has been challenging. Here, we used CRISPRi-mediated silencing of the histone methyltransferase SETDB1 to remove H3K9me3 heterochromatin in human neural progenitor cells. Despite a major loss of H3K9me3 peaks resulting in genome-wide reorganization of heterochromatin domains, silencing of SETDB1 had a limited effect on cell viability. Cells remained proliferative and expressed appropriate marker genes. We found that a key event following the loss of SETDB1-mediated H3K9me3 was the expression of evolutionarily young L1 retrotransposons. Derepression of L1s was associated with a loss of CpG DNA methylation at their promoters, suggesting that deposition of H3K9me3 at the L1 promoter is required to maintain DNA methylation. In conclusion, these results demonstrate that loss of H3K9me3 in human neural somatic cells transcriptionally activates evolutionary young L1 retrotransposons.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nucleic Acids Research
volume
54
issue
4
article number
gkag100
publisher
Oxford University Press
external identifiers
  • pmid:41641702
  • scopus:105029612728
ISSN
0305-1048
DOI
10.1093/nar/gkag100
language
English
LU publication?
yes
id
f282780c-0e0e-4c60-aaaf-91f2a42d7f76
date added to LUP
2026-04-17 13:16:12
date last changed
2026-04-18 03:20:17
@article{f282780c-0e0e-4c60-aaaf-91f2a42d7f76,
  abstract     = {{<p>Heterochromatin is characterized by an inaccessibility to the transcriptional machinery and is associated with the histone mark H3K9me3. However, studying the functional consequences of heterochromatin loss in human cells has been challenging. Here, we used CRISPRi-mediated silencing of the histone methyltransferase SETDB1 to remove H3K9me3 heterochromatin in human neural progenitor cells. Despite a major loss of H3K9me3 peaks resulting in genome-wide reorganization of heterochromatin domains, silencing of SETDB1 had a limited effect on cell viability. Cells remained proliferative and expressed appropriate marker genes. We found that a key event following the loss of SETDB1-mediated H3K9me3 was the expression of evolutionarily young L1 retrotransposons. Derepression of L1s was associated with a loss of CpG DNA methylation at their promoters, suggesting that deposition of H3K9me3 at the L1 promoter is required to maintain DNA methylation. In conclusion, these results demonstrate that loss of H3K9me3 in human neural somatic cells transcriptionally activates evolutionary young L1 retrotransposons.</p>}},
  author       = {{Karlsson, Ofelia and Pandiloski, Ninoslav and Horvath, Vivien and Adami, Anita and Garza, Raquel and Johansson, Pia A. and Johansson, Jenny G. and Douse, Christopher H. and Jakobsson, Johan}},
  issn         = {{0305-1048}},
  language     = {{eng}},
  number       = {{4}},
  publisher    = {{Oxford University Press}},
  series       = {{Nucleic Acids Research}},
  title        = {{Loss of SETDB1-mediated H3K9me3 in human neural progenitor cells leads to transcriptional activation of L1 retrotransposons}},
  url          = {{http://dx.doi.org/10.1093/nar/gkag100}},
  doi          = {{10.1093/nar/gkag100}},
  volume       = {{54}},
  year         = {{2026}},
}