Dual Chromatin Repressors Regulate Hippocampal Development

The cell fate transition from radial glial-like (RGL) cells to neurons and astrocytes is crucial for development and pathological conditions. Two chromatin repressors- the enhancer of zeste homolog 2 and suppressor of variegation 4-20 homolog, are highly associated with RGL cells in the hippocampus, implicating hippocampal cell fate commitment underlying these epigenetic regulations. Using a double knock-out mouse model, we demonstrated that loss of both chromatin repressors in the RGL population leads to deficits in hippocampal development. At the molecular level, single nuclei RNA-Seq revealed differential gene expression and provided mechanistic insight that dual chromatin repressors are critical for the maintenance of cycling cells in the dentate gyrus as well as the balance of cell trajectories between neuronal and astroglial lineages. Linked flow cytometry and single-nuclei RNAseq datasets from wild-type and double knock-out of Ezh2 and Suv4-20h mice brains放射状胶质样细胞（radial glial-like cells, RGL）向神经元与星形胶质细胞的命运转变，对于机体发育及病理状态均至关重要。两种染色质阻遏因子——zeste同源增强子2（enhancer of zeste homolog 2, Ezh2）与异染色质蛋白4-20同源物（suppressor of variegation 4-20 homolog, Suv4-20h）——在海马体的RGL细胞中高表达，提示上述表观遗传调控机制参与了海马细胞的命运决定过程。本研究借助双基因敲除小鼠模型证实，在RGL细胞群体中同时缺失这两种染色质阻遏因子，会引发海马发育缺陷。在分子层面，单细胞核RNA测序（single nuclei RNA-Seq）揭示了差异基因表达谱，并提供了机制层面的解析：双染色质阻遏因子对于维持齿状回的增殖细胞群体，以及神经元与星形胶质细胞谱系间的细胞轨迹平衡均发挥关键作用。本数据集关联了野生型与Ezh2、Suv4-20h双基因敲除小鼠脑组织的流式细胞术（flow cytometry）与单细胞核RNA测序数据。