Loss of Ezh2 in the medial ganglionic eminence alters interneuron fate, cell morphology and gene expression profiles
Rhodes, C. T.; Asokumar, D.; Sohn, M.; Naskar, S.; Elisha, L.; Stevenson, P.; Lee, D. R.; Zhang, Y.; Rocha, P. P.; Dale, R. K.; Lee, S.; Petros, T. J.
Show abstract
Enhancer 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 of Ezh2 increases 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 in Ezh2 mutant 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.
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