NSD2 Coordinates the Neurogenic‐to‐Gliogenic Transition via H3K36me2‐Dependent Activation of the EGFR‐ERK Pathway

Abstract

ABSTRACT Haploinsufficiency of the histone methyltransferase NSD2 is a major cause of Wolf‐Hirschhorn syndrome (WHS) and the related Rauch‐Steindl syndrome (RAUST), both of which exhibit microcephaly and intellectual disability. However, the precise role of NSD2 in brain development remains unclear. Here, we identify NSD2 as a pivotal epigenetic regulator orchestrating the transition from neurogenesis to gliogenesis in the developing mouse neocortex. Conditional knockout of Nsd2 severely impairs astrocyte production in late embryogenesis, while its overexpression promotes astrocytic fate. Integrated epigenomic and transcriptomic analyses reveal that NSD2 deposits the activating histone mark H3K36me2 directly at the Egfr promoter, sustaining EGFR expression and downstream ERK signaling—a pathway essential for gliogenesis. Pharmacological activation of ERK phosphorylation rescues the astrogliogenesis defects both in vitro and in vivo. Notably, Nsd2‐deficient mice exhibit significant deficits in learning and memory. Our findings define an NSD2‐H3K36me2‐EGFR‐ERK axis that drives cortical gliogenesis and provide mechanistic insights into the potential contribution of NSD2 deficiency to neurodevelopmental abnormalities.