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.
A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development / Johansson, P. A.; Brattas, P. L.; Douse, C. H.; Hsieh, P.; Adami, A.; Pontis, J.; Grassi, D.; Garza, R.; Sozzi, E.; Cataldo, R.; Jonsson, M. E.; Atacho, D. A. M.; Pircs, K.; Eren, F.; Sharma, Y.; Johansson, J.; Fiorenzano, A.; Parmar, M.; Fex, M.; Trono, D.; Eichler, E. E.; Jakobsson, J.. - In: CELL STEM CELL. - ISSN 1934-5909. - 29:1(2022), pp. 52-69.e8. [10.1016/j.stem.2021.09.008]
A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development
Cataldo R.;Fiorenzano A.;
2022
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
