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

• Published in: Cell stem cell Vol. 29; no. 1; pp. 52 - 69.e8
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.01.2022
• Subjects: Basic Medicine; Biologi; Biological Sciences; Brain - metabolism; brain development; chimpanzee; CRISPRi; DNA-Binding Proteins; evolution; forebrain neural progenitors; Gene Expression Regulation; Gene Regulatory Networks; Genetics; Genetik; human; Humans; KRAB-ZNFs; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Natural Sciences; Naturvetenskap; Neurosciences; Neurovetenskaper; Organoids - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; transposable elements; KRAB-ZNFs; brain development; CRISPRi; chimpanzee; evolution; transposable elements; human; forebrain neural progenitors
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2021.09.008

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. [Display omitted] •ZNF558 is uniquely expressed in human but not chimpanzee forebrain progenitors•ZNF558 has been co-opted to control the expression of a single gene, SPATA18•ZNF558 plays a role in mitochondrial homeostasis and brain development•ZNF558 expression is controlled by the size of a downstream VNTR Johansson et al. identify ZNF558, a KRAB-ZFP expressed in human but not chimpanzee forebrain progenitors, where it regulates its target SPATA18. The expression of ZNF558 is controlled by the size of a VNTR that is longer in chimpanzees compared to humans, demonstrating a role for structural variations in human brain evolution.