A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development
(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.
(Less)
- author
- organization
-
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- Molecular Neurogenetics (research group)
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Center for Translational Genomics (CTG)
- LUCC: Lund University Cancer Centre
- Translational Genomic and Functional Studies of Leukemia (research group)
- Division of Clinical Genetics
- Epigenetics and Chromatin Dynamics (research group)
- Developmental and Regenerative Neurobiology (research group)
- Diabetes - Molecular Metabolism (research group)
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cell Stem Cell
- volume
- 29
- issue
- 1
- pages
- 8 - 69
- publisher
- Cell Press
- external identifiers
-
- pmid:34624206
- scopus:85121989721
- 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
- 2024-09-22 03:25:59
@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}}, }