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

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 and Guangjin Pan ()
Additional contact information
Yongli Shan: Guangzhou Medical University
Yanqi Zhang: Guangzhou Medical University
Yuan Zhao: Guangzhou Medical University
Tianyu Wang: Guangzhou Medical University
Jingyuan Zhang: Guangzhou Medical University
Jiao Yao: Guangzhou Medical University
Ning Ma: Guangzhou Medical University
Zechuan Liang: Guangzhou Medical University
Wenhao Huang: Guangzhou Medical University
Ke Huang: Guangzhou Medical University
Tian Zhang: Guangzhou Medical University
Zhenghui Su: Guangzhou Medical University
Qianyu Chen: Guangzhou Medical University
Yanling Zhu: Guangzhou Medical University
Chuman Wu: Guangzhou Medical University
Tiancheng Zhou: Guangzhou Medical University
Wei Sun: Guangzhou Medical University
Yanxing Wei: Southern Medical University
Cong Zhang: Guangzhou Medical University
Chenxu Li: Guangzhou Medical University
Shuquan Su: Guangzhou Medical University
Baojian Liao: Guangzhou Medical University
Mei Zhong: Southern Medical University
Xiaofen Zhong: Guangzhou Medical University
Jinfu Nie: Guangzhou Medical University
Duanqing Pei: Guangzhou Medical University
Guangjin Pan: Guangzhou Medical University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Neurogenesis, 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.

Date: 2020
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DOI: 10.1038/s41467-019-14028-x

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