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 Hernandez-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

doi:10.1126/science.adv2861

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 Hernandez-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^*

^*Corresponding author for this work

Oncode Institute
Netherlands Cancer Institute
University of Oxford
Radboud University Nijmegen

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	eadv2861
Journal	Science
Volume	389
Issue number	6755
DOIs	https://doi.org/10.1126/science.adv2861
Publication status	Published - 3 Jul 2025

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Bianchi, D., Borza, R., de Zan, E., Huelsz-Prince, G., Gregoricchio, S., Dekker, M., Fish, A., Mazouzi, A., Kroese, L. J., Linder, S., Hernandez-Quiles, M., Vermeulen, M., Celie, P. H. N., Krimpenfort, P., Song, J.-Y., Zwart, W., Wessels, L., Nijman, S. M. B., Perrakis, A., & Brummelkamp, T. R. (2025). Zincore, an atypical coregulator, binds zinc finger transcription factors to control gene expression. Science, 389(6755), Article eadv2861. https://doi.org/10.1126/science.adv2861

@article{01c31d8549734d27aa28bff93e22fed3,

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

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.",

author = "Dani{\"e}lle Bianchi and Razvan Borza and \{de Zan\}, Erica and Guizela Huelsz-Prince and Sebastian Gregoricchio and Marleen Dekker and Alex Fish and Abdelghani Mazouzi and Kroese, \{Lona J.\} and Simon Linder and Miguel Hernandez-Quiles and Michiel Vermeulen and Celie, \{Patrick H. N.\} and Paul Krimpenfort and Ji-Ying Song and Wilbert Zwart and Lodewyk Wessels and Nijman, \{Sebastian M. B.\} and Anastassis Perrakis and Brummelkamp, \{Thijn R.\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 the authors, some rights reserved.",

year = "2025",

month = jul,

day = "3",

doi = "10.1126/science.adv2861",

language = "English",

volume = "389",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6755",

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Bianchi, D, Borza, R, de Zan, E, Huelsz-Prince, G, Gregoricchio, S, Dekker, M, Fish, A, Mazouzi, A, Kroese, LJ, Linder, S, Hernandez-Quiles, M, Vermeulen, M, Celie, PHN, Krimpenfort, P, Song, J-Y, Zwart, W, Wessels, L, Nijman, SMB, Perrakis, A & Brummelkamp, TR 2025, 'Zincore, an atypical coregulator, binds zinc finger transcription factors to control gene expression', Science, vol. 389, no. 6755, eadv2861. https://doi.org/10.1126/science.adv2861

TY - JOUR

T1 - Zincore, an atypical coregulator, binds zinc finger transcription factors to control gene expression

AU - Bianchi, Daniëlle

AU - Borza, Razvan

AU - de Zan, Erica

AU - Huelsz-Prince, Guizela

AU - Gregoricchio, Sebastian

AU - Dekker, Marleen

AU - Fish, Alex

AU - Mazouzi, Abdelghani

AU - Kroese, Lona J.

AU - Linder, Simon

AU - Hernandez-Quiles, Miguel

AU - Vermeulen, Michiel

AU - Celie, Patrick H. N.

AU - Krimpenfort, Paul

AU - Song, Ji-Ying

AU - Zwart, Wilbert

AU - Wessels, Lodewyk

AU - Nijman, Sebastian M. B.

AU - Perrakis, Anastassis

AU - Brummelkamp, Thijn R.

PY - 2025/7/3

Y1 - 2025/7/3

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105010600210

U2 - 10.1126/science.adv2861

DO - 10.1126/science.adv2861

M3 - Article

C2 - 40608935

SN - 0036-8075

VL - 389

JO - Science

JF - Science

IS - 6755

M1 - eadv2861

ER -

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

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