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

Zinc finger proteins (ZNFs) are the largest family of transcription factors, yet how they activate gene expression and whether they require dedicated coactivators remains unclear. Here, we identify and study Zincore, an uncharacterized protein complex consisting of QRICH1 and SEPHS1, as a novel ZNF-specific coactivator. Both QRICH1 and SEPHS1 are critical for embryonic development in mice and their haploinsufficiency is linked to similar neurodevelopmental defects in humans. Among Zincore clients, we identify ZFP91 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 Zincore to recognise the DNA-bound zinc finger domains, explaining the recognition of a wide variety of ZNFs. Surprisingly, this interaction stabilizes the binding of ZFP91 to the DNA, thereby locking it on its consensus motif, providing a unique activity for a coactivator. Thus, our study reveals Zincore as ZNF-specific coactivator essential for embryonic development, involving an unprecedented mechanism to lock ZNFs onto DNA and regulate transcription.