Zincore, an atypical coregulator, binds zinc finger transcription factors to control gene expression
- Daniëlle Bianchi
- Razvan Borza
- Erica De Zan
- Guizela Huelsz-Prince
- Sebastian Gregoricchio
- Marleen Dekker
- Alex Fish
- Abdelghani Mazouzi
- Lona J. Kroese
- Simon Linder
- Miguel Hernández-Quiles
- Michiel Vermeulen
- Patrick H. N. Celie
- Paul Krimpenfort
- Ji-Ying Song
- Wilbert Zwart
- Lodewyk Wessels
- Sebastian M. B. Nijman
- Anastassis Perrakis
- Thijn R. Brummelkamp
2025-07-03
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.