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

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-07-03 DOI:10.1126/science.adv2861

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

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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.

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Zincore是一种非典型的共调节因子，结合锌指转录因子控制基因表达

锌指蛋白（ZNFs）是最大的转录因子家族，但它们如何激活基因表达尚不清楚。在这项研究中，我们确定了Zincore，一种由QRICH1和SEPHS1组成的蛋白复合物，是小鼠胚胎发育所必需的znf特异性共调节因子，并与人类发育综合征相关。我们还将ZFP91确定为具有代表性的Zincore客户，它结合了保守的启动子基元CTTTAAR。Zincore-ZFP91-DNA复合体的低温电子显微镜显示SEPHS1精氨酸钳可以识别dna结合的锌指结构域。这种结合模式解释了对不同ZNFs的识别，并将ZFP91稳定在其同源DNA基序上。因此，我们的研究确定了Zincore是发育所必需的znf特异性共调节因子，涉及将znf锁定在DNA上并调节转录的独特机制。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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