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A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development

Johansson, Pia A LU ; Brattås, Per Ludvik LU ; Douse, Christopher H LU ; Hsieh, PingHsun ; Adami, Anita LU orcid ; Pontis, Julien ; Grassi, Daniela LU ; Garza, Raquel LU orcid ; Sozzi, Edoardo LU orcid and Cataldo, Rodrigo LU orcid , et al. (2022) In Cell Stem Cell 29(1). p.8-69
Abstract

The human forebrain has expanded in size and complexity compared to chimpanzees despite limited changes in protein-coding genes, suggesting that gene expression regulation is an important driver of brain evolution. Here, we identify a KRAB-ZFP transcription factor, ZNF558, that is expressed in human but not chimpanzee forebrain neural progenitor cells. ZNF558 evolved as a suppressor of LINE-1 transposons but has been co-opted to regulate a single target, the mitophagy gene SPATA18. ZNF558 plays a role in mitochondrial homeostasis, and loss-of-function experiments in cerebral organoids suggests that ZNF558 influences developmental timing during early human brain development. Expression of ZNF558 is controlled by the size of a variable... (More)

The human forebrain has expanded in size and complexity compared to chimpanzees despite limited changes in protein-coding genes, suggesting that gene expression regulation is an important driver of brain evolution. Here, we identify a KRAB-ZFP transcription factor, ZNF558, that is expressed in human but not chimpanzee forebrain neural progenitor cells. ZNF558 evolved as a suppressor of LINE-1 transposons but has been co-opted to regulate a single target, the mitophagy gene SPATA18. ZNF558 plays a role in mitochondrial homeostasis, and loss-of-function experiments in cerebral organoids suggests that ZNF558 influences developmental timing during early human brain development. Expression of ZNF558 is controlled by the size of a variable number tandem repeat that is longer in chimpanzees compared to humans, and variable in the human population. Thus, this work provides mechanistic insight into how a cis-acting structural variation establishes a regulatory network that affects human brain evolution.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell Stem Cell
volume
29
issue
1
pages
8 - 69
publisher
Cell Press
external identifiers
  • scopus:85121989721
  • pmid:34624206
ISSN
1934-5909
DOI
10.1016/j.stem.2021.09.008
language
English
LU publication?
yes
additional info
Copyright © 2021 The Author(s). Published by Elsevier Inc.
id
b78aae61-c5c5-4cb5-8d81-21ac22d249f1
date added to LUP
2021-10-19 14:03:25
date last changed
2024-06-16 21:08:57
@article{b78aae61-c5c5-4cb5-8d81-21ac22d249f1,
  abstract     = {{<p>The human forebrain has expanded in size and complexity compared to chimpanzees despite limited changes in protein-coding genes, suggesting that gene expression regulation is an important driver of brain evolution. Here, we identify a KRAB-ZFP transcription factor, ZNF558, that is expressed in human but not chimpanzee forebrain neural progenitor cells. ZNF558 evolved as a suppressor of LINE-1 transposons but has been co-opted to regulate a single target, the mitophagy gene SPATA18. ZNF558 plays a role in mitochondrial homeostasis, and loss-of-function experiments in cerebral organoids suggests that ZNF558 influences developmental timing during early human brain development. Expression of ZNF558 is controlled by the size of a variable number tandem repeat that is longer in chimpanzees compared to humans, and variable in the human population. Thus, this work provides mechanistic insight into how a cis-acting structural variation establishes a regulatory network that affects human brain evolution.</p>}},
  author       = {{Johansson, Pia A and Brattås, Per Ludvik and Douse, Christopher H and Hsieh, PingHsun and Adami, Anita and Pontis, Julien and Grassi, Daniela and Garza, Raquel and Sozzi, Edoardo and Cataldo, Rodrigo and Jönsson, Marie E and Atacho, Diahann A M and Pircs, Karolina and Eren, Feride and Sharma, Yogita and Johansson, Jenny and Fiorenzano, Alessandro and Parmar, Malin and Fex, Malin and Trono, Didier and Eichler, Evan E and Jakobsson, Johan}},
  issn         = {{1934-5909}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{8--69}},
  publisher    = {{Cell Press}},
  series       = {{Cell Stem Cell}},
  title        = {{A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development}},
  url          = {{http://dx.doi.org/10.1016/j.stem.2021.09.008}},
  doi          = {{10.1016/j.stem.2021.09.008}},
  volume       = {{29}},
  year         = {{2022}},
}