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 <i>Phf23</i> knock-out (<i>Phf2</i>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 <i>Tcf4</i> and <i>Eya1</i> Overexpression of <i>Tcf4</i> rescues the differentiation defects of <i>Phf2</i>3-KO NSCs. These results establish PHF23 as a pivotal regulator of neurogenesis, indicating cell type-specific functions of PHD finger proteins.