A human-specific structural variation at theZNF558locus controls a gene regulatory network during forebrain development

Abstract

The human forebrain has expanded in size and complexity compared to that of chimpanzee despite limited changes in protein-coding genes, suggesting that gene 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 the mitophagy gene SPATA18, supporting a link between mitochondrial homeostasis and cortical expansion. The unusual on-off switch for ZNF558 expression resides in a downstream variable number tandem repeat (VNTR) that is contracted in humans relative to chimpanzee. Our data reveal the brain-specific co-option of a transposon-controlling KRAB-ZFP and how a human-specific regulatory network is established by a cis-acting structural genome variation. This represents a previously undescribed genetic mechanism in the evolution of the human brain.

JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles

“…A potential contributing challenge to obtaining orthogonal evidence may be the fact that many zinc-fingers, which represent the largest class of TFs, have been reported to regulate a limited number or even a single gene (e.g. Zfp568 ( 64 ), ZNF558 ( 65 ), ZNF410 ( 66 ) and ZFP64 ( 67 )).…”

Harnessing pluripotent stem cells as models to decipher human evolution

“…It is to this question, therefore, that inter-species iPSC models have been applied most frequently (see Mostajo-Radj et al [125] for an extensive review of this field). In the absence of primary tissue, which is hard to obtain and stage, several studies have used iPSCderived brain cell types using 2D culture differentiation protocols from different developmental time points in an attempt to explore differences that can be linked to human-specific cognition [122,[126][127][128][129][130][131][132][133]. For example, Otani et al made elegant use of the staged nature of a 2D cortical development protocol [134] to examine cortical cell proliferation across humans, chimpanzees and macaques, finding differences in the amount of time cortical progenitor cells remained proliferative across the three species [129] that could potentially be linked to differences in brain cell numbers between them.…”

“…[125] for an extensive review of this field). In the absence of primary tissue, which is hard to obtain and stage, several studies have used iPSC‐derived brain cell types using 2D culture differentiation protocols from different developmental time points in an attempt to explore differences that can be linked to human‐specific cognition [122,126–133]. For example, Otani et al .…”

Genomic approaches to trace the history of human brain evolution with an emerging opportunity for transposon profiling of ancient humans

“…Rather than completely silencing transcription of TEs in embryogenesis, KZFPs such as ZNF417 and ZNF587 (absent in mouse) control regulatory sequences consisting of exapted TEs, and consequently affect expression of hundreds of human genes in developing and adult human brain [90]. As an unexpected outcome from the evolutionary arms race to repress expression of evolving L1 sequences, a KZFP transcription factor ZNF558 (highly expressed in human but not in chimpanzee forebrain neural progenitor cells) has been exapted to repress mitophagy and potentially contribute to human-specific cortical expansion [91]. More examples of TE and KZFP's contribution to species-specific mammalian development are recently reviewed by Senft and Macfarlan [14].…”

“…For example, CRISPR/Cas9 excision of a pathogenic TE insertion in patient iPSCs rescued molecular phenotypes in neural stem cells and differentiated neurons [176]. iPSCs and neuronal progenitor cells (NPCs) from chimpanzee and other primates have been generated to probe cellular and molecular differences between human and NHPs [80,91]. Leveraging recent innovations in iPSC-derived brain organoids for 3D modeling, researchers can investigate TE insertion-induced phenotypical changes during early cortical development [177].…”