e-Article
A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development
Document Type
Author
Johansson, Pia A; Brattås, Per Ludvik; Douse, Christopher H; Hsieh, PingHsun; Adami, Anita; Pontis, Julien; Grassi, Daniela; Garza, Raquel; Sozzi, Edoardo; Cataldo, Rodrigo; Jönsson, Marie E; Atacho, Diahann A M; Pircs, Karolina; Eren, Feride; Sharma, Yogita; Johansson, Jenny; Fiorenzano, Alessandro; Parmar, Malin; Fex, Malin; Trono, Didier; Eichler, Evan E; Jakobsson, Johan
Source
Cell Stem Cell MultiPark: Multidisciplinary research focused on Parkinson´s disease StemTherapy: National Initiative on Stem Cells for Regenerative Therapy. 29(1):8-69
Subject
Language
English
ISSN
1934-5909
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 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.