JMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells

• DOI: 10.1038/s41467-019-14028-x
• Publication Date: 2020-01-20T11:03:19Z
• Authors: Yongli Shan; Yanqi Zhang; Yuan Zhao; Tianyu Wang; Jingyuan Zhang; Jiao Yao; Ning Ma; Zechuan Liang; Wenhao Huang; Ke Huang; Tian Zhang; Zhenghui Su; Qianyu Chen; Yanling Zhu; Chuman Wu; Tiancheng Zhou; Wei Sun; Yanxing Wei; Cong Zhang; Chenxu Li; Shuquan Su; Baojian Liao; Mei Zhong; Xiaofen Zhong; Jinfu Nie; Duanqing Pei; Guangjin Pan
• Keywords: Histone Demethylases; Jumonji Domain-Containing Histone Demethylases; 0303 health sciences; Science; Neurogenesis; Q; Gene Expression Regulation, Developmental; Cell Differentiation; DNA Methylation; Article; Cell Line; Epigenesis, Genetic; DNA-Binding Proteins; Histones; Gene Knockout Techniques; 03 medical and health sciences; Neural Stem Cells; Humans; Gene Knock-In Techniques; RNA-Seq; Embryonic Stem Cells; Cell Proliferation

AbstractNeurogenesis, a highly orchestrated process, entails the transition from a pluripotent to neural state and involves neural progenitor cells (NPCs) and neuronal/glial subtypes. However, the precise epigenetic mechanisms underlying fate decision remain poorly understood. Here, we delete KDM6s (JMJD3 and/or UTX), the H3K27me3 demethylases, in human embryonic stem cells (hESCs) and show that their deletion does not impede NPC generation from hESCs. However, KDM6-deficient NPCs exhibit poor proliferation and a failure to differentiate into neurons and glia. Mechanistically, both JMJD3 and UTX are found to be enriched in gene loci essential for neural development in hNPCs, and KDM6 impairment leads to H3K27me3 accumulation and blockade of DNA accessibility at these genes. Interestingly, forced expression of neuron-specific chromatin remodelling BAF (nBAF) rescues the neuron/glia defect in KDM6-deficient NPCs despite H3K27me3 accumulation. Our findings uncover the differential requirement of KDM6s in specifying NPCs and neurons/glia and highlight the contribution of individual epigenetic regulators in fate decisions in a human development model.