Loss of Ezh2 in the medial ganglionic eminence alters interneuron fate, cell morphology and gene expression profiles

Abstract

SUMMARYEnhancer of zeste homolog 2 (Ezh2) is responsible for trimethylation of histone 3 at lysine 27 (H3K27me3), resulting in gene repression. Here, we explore the role of Ezh2 in forebrain GABAergic interneuron development. Loss ofEzh2increases somatostatin-expressing (SST+) and decreases parvalbumin-expressing (PV+) interneurons in multiple brain regions. We also observe fewer MGE-derived interneurons in the first postnatal week, indicating reduced interneuron production. Intrinsic electrophysiological properties in SST+ and PV+ interneurons are normal, but PV+ interneurons display increased axonal complexity inEzh2mutant mice. Single cell multiome analysis revealed differential gene expression patterns in the embryonic MGE that are predictive of these cell fate changes. Lastly, CUT&Tag analysis revealed differential H3K27me3 levels at specific genomic loci, with some genes displaying a relative increase in H3K27me3 indicating they may be resistant to epigenetic modifications. Thus, loss of Ezh2 in the MGE alters interneuron fate, morphology, and gene expression and regulation.