Rhodes Christopher T, Asokumar Dhanya, Sohn Mira, Naskar Shovan, Elisha Lielle, Stevenson Parker, Lee Dongjin R, Zhang Yajun, Rocha Pedro P, Dale Ryan K, Lee Soohyun, Petros Timothy J
Unit on Cellular and Molecular Neurodevelopment, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, United States.
Unit on Genome Structure and Regulation, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, United States.
Front Cell Neurosci. 2024 Feb 14;18:1334244. doi: 10.3389/fncel.2024.1334244. eCollection 2024.
Enhancer of zeste homolog 2 (Ezh2) is responsible for trimethylation of histone 3 at lysine 27 (H3K27me3), resulting in repression of gene expression. Here, we explore the role of Ezh2 in forebrain GABAergic interneuron development.
We removed in the MGE by generating conditional knockout mice. We then characterized changes in MGE-derived interneuron fate and electrophysiological properties in juvenile mice, as well as alterations in gene expression, chromatin accessibility and histone modifications in the MGE.
Loss of increases somatostatin-expressing (SST+) and decreases parvalbumin-expressing (PV+) interneurons in the forebrain. We 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 mutant mice. Single nuclei multiome analysis revealed differential gene expression patterns in the embryonic MGE that are predictive of these cell fate changes. Lastly, CUT&Tag analysis revealed that some genomic loci are particularly resistant or susceptible to shifts in H3K27me3 levels in the absence of , indicating differential selectivity to epigenetic perturbation.
Thus, loss of Ezh2 in the MGE alters interneuron fate, morphology, and gene expression and regulation. These findings have important implications for both normal development and potentially in disease etiologies.
zeste 同源物 2 增强子（Ezh2）负责组蛋白 3 赖氨酸 27 位点的三甲基化（H3K27me3），导致基因表达受到抑制。在此，我们探讨 Ezh2 在大脑前脑γ-氨基丁酸能中间神经元发育中的作用。
我们通过构建条件性敲除小鼠，在中脑腹侧神经节（MGE）中敲除 Ezh2。然后，我们对幼年小鼠中 MGE 衍生的中间神经元命运和电生理特性的变化进行了表征，以及对 MGE 中的基因表达、染色质可及性和组蛋白修饰的改变进行了研究。
Ezh2 的缺失增加了前脑中表达生长抑素（SST+）的中间神经元数量，并减少了表达小白蛋白（PV+）的中间神经元数量。我们观察到出生后第一周 MGE 衍生的中间神经元数量减少，表明中间神经元生成减少。SST+和 PV+中间神经元的内在电生理特性正常，但在 Ezh2 突变小鼠中，PV+中间神经元的轴突复杂性增加。单核多组学分析揭示了胚胎 MGE 中不同的基因表达模式，这些模式可预测这些细胞命运的变化。最后，CUT&Tag 分析表明，在没有 Ezh2 的情况下，一些基因组位点对 H3K27me3 水平的变化特别有抗性或敏感性，表明对表观遗传扰动的选择性不同。
因此，MGE 中 Ezh2 的缺失改变了中间神经元的命运、形态以及基因表达和调控。这些发现对正常发育以及潜在的疾病病因学都具有重要意义。
