Abstract - Zinc finger proteins (ZNFs) are the largest family of transcription factors, yet how theyactivate gene expression remains unclear. Here, we identify and study Zincore, an uncharacterizedprotein complex consisting of QRICH1 and SEPHS1, as a novel ZNF-specific coregulator. BothQRICH1 and SEPHS1 are critical for embryonic development in mice and their haploinsufficiencyis linked to similar neurodevelopmental defects in humans. Among Zincore clients, we identifyZFP91 as the transcription factor that binds to the evolutionary conserved motif CTTTAAR. The cryo-EM structure of Zincore in complex with ZFP91 bound to this motif, reveals Zincoreto recognise the DNA-bound zinc finger domains, explaining the recognition of a wide variety ofZNFs. Surprisingly, this interaction stabilizes the binding of ZFP91 to the DNA, thereby lockingit on its consensus motif, providing a unique activity for a transcriptional coregulator. Thus, ourstudy reveals Zincore as ZNF-specific coregulator essential for embryonic development, involvingan unprecedented mechanism to lock ZNFs onto DNA and regulate transcription. This is the author's version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on July 4th 2025, DOI: DOI: 10.1126/science.adv2861