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A novel KRAB zinc finger gene has changed the balance of HES1 autoregulation during primate evolution

ABSTRACT: KRAB zinc finger (KZNF) proteins are a class of transcriptional repressors important for epigenetic silencing of specific genomic regions. About 170 primate-specific KZNFs are present in the human genome. While KZNFs are primarily associated with repressing retrotransposon-derived DNA, evidence is emerging that they can be co-opted for other gene regulatory processes. We focused on the 19p12 locus, which shows copy-number variations associated with neurodevelopmental disorders, implying it is required for human brain development. The two genes in this locus, ZNF675 and ZNF681, arose via duplication in primates. Genetic deletion of ZNF675 caused developmental defects in cortical organoids and our data suggest that the observed neurodevelopmental phenotype is mediated by ZNF675 binding to the promoter of the neurodevelopmental gene HES1. We show that ZNF675 interferes with HES1 auto-inhibition, a process essential for maintenance of neural progenitors. As a striking example of how some KZNFs have integrated into pre-existing gene expression networks, these findings suggest the emergence of ZNF675 has caused a change in balance of HES1 autoregulation. The association of ZNF675 CNV with human developmental disorders suggests that this new balance has become essential for normal human brain development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166471 | GEO | 2021/02/10

REPOSITORIES: GEO

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