The epigenetic reader PHF23 is required for embryonic neurogenesis

Epigenetic mechanisms are crucial in the tightly regulated process of neurogenesis from radial glial cells (RGCs) to intermediate progenitor cells (IPCs) to neurons during embryonic brain development. Plant homeodomain (PHD) finger proteins as important epigenetic readers are implicated in development and diseases, yet their roles in embryonic neurogenesis remain largely unexplored. In this study, we found different PHD finger proteins are differentially expressed along the neurogenesis trajectory. Among them, we investigated the function of PHF23 using mouse models, which is highly expressed in RGCs and IPCs, but not in neurons. Our findings demonstrate that PHF23 is essential for proper neurogenesis, and Phf23 knockout ( Phf2 3-KO) results in cortical developmental defects due to differentiation blockade of RGCs. Mechanistically, PHF23 bind with HDAC2, inhibiting its deacetylation activity on the active histone mark H3K27ac, thereby promoting the expression of neuronal differentiation pathway genes such as Tcf4 and Eya1 . Overexpression of Tcf4 rescues the differentiation defects of Phf2 3-KO NSCs. These results establish PHF23 as a pivotal regulator of neurogenesis, indicating cell type-specific functions of PHD finger proteins. Significance Statement Epigenetic regulation of neurogenesis is orchestrated by writers, readers, and erasers of histone codes, however, the roles of a class of epigenetic writers, PHD finger proteins, remain largely unexplored. We have systematically explored their expression patterns using single-cell datasets and revealed the essential role and underlying molecular mechanism of PHF23 in regulating the differentiation of embryonic neural stem cells, using genetic models, RNA-seq and CUT&TAG, and functional assays, shedding light on cell-type specific functions of PHD figure proteins.