Zincore, an atypical coregulator, binds zinc finger transcription factors to control gene expression

Science. 2025 Jul 3;389(6755):eadv2861. doi: 10.1126/science.adv2861. Epub 2025 Jul 3.

Abstract

Zinc finger proteins (ZNFs) are the largest family of transcription factors, yet how they activate gene expression remains unclear. In this study, we identified Zincore, a protein complex consisting of QRICH1 and SEPHS1, as a ZNF-specific coregulator essential for embryonic development in mice and associated with developmental syndromes in humans. We also identified ZFP91 as a representative Zincore client, binding the conserved promoter motif CTTTAAR. Cryo-electron microscopy of a Zincore-ZFP91-DNA complex revealed a SEPHS1 arginine clamp to recognize the DNA-bound zinc finger domains. This mode of binding explains recognition of different ZNFs and stabilizes ZFP91 onto its cognate DNA motif. Thus, our study identified Zincore as a ZNF-specific coregulator essential for development, involving a distinctive mechanism that locks ZNFs onto DNA and regulates transcription.

MeSH terms

  • Animals
  • Carrier Proteins* / chemistry
  • Carrier Proteins* / metabolism
  • Cryoelectron Microscopy
  • DNA / chemistry
  • DNA / metabolism
  • DNA-Binding Proteins* / chemistry
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Embryonic Development / genetics
  • Gene Expression Regulation, Developmental*
  • Humans
  • Mice
  • Multiprotein Complexes* / chemistry
  • Multiprotein Complexes* / genetics
  • Multiprotein Complexes* / metabolism
  • Phosphotransferases* / chemistry
  • Phosphotransferases* / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Transcription Factors* / chemistry
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Transcription, Genetic
  • Zinc Fingers*

Substances

  • Carrier Proteins
  • DNA
  • DNA-Binding Proteins
  • Transcription Factors
  • Multiprotein Complexes
  • QRICH1 protein, human
  • SEPHS1 protein, human
  • Phosphotransferases