Scientists discovers the essential role of H3K27me3 demethylases KDM6 in human neurogenesis

Prof. PAN Guangjin and his colleagues, researchers from Guangzhou Institute of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), have discovered the essential and universal role of H3K27me3 demethylases KDM6 (JMJD3 and UTX) in maintaining proliferation capability and multi-differentiation potential of human neural progenitor cells. The study titled "JMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells" was recently published in Nature Communications(https://www.nature.com/ncomms/). 

Neurogenesis, a highly orchestrated process, entails the transition from a pluripotent to neural state and involves neural progenitor cells (NPCs) and neuronal/glial subtypes and plays a critical role in early human embryonic development. However, the precise epigenetic mechanisms underlying fate decision remain poorly understood. In 2017, Prof. PAN group reported the critical role of H3K27me3 methyltransferases polycomb repressive complex 2 (PRC2) in specifying human neuro-ectoderm in Nature Communications. But, the role and their precisely mechanisms of H3K27me3 demethylases KDM6 family (JMJD3/KDM6B and UTX/KDM6A) in determining lineage specification and fate transition from human PSCs to neural progenitor cells (NPCs) and then subtypes of neural cells remains largely unknown. 

Scientists 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. 

This study reveals the previously unknown but essential role of KDM6s-dependent H3K27me3 demethylation in specifying lineage fidelity and fate decision in human neurogenesis. Prof. PAN group’s recent report showed that PRC2 is clearly required to specify NPCs from human PSCs. Their serial findings reveal the differential requirement of the methylation and de-methylation of H3K27me3 during sequential lineage specification from pluripotency to neural subtypes in human neurogenesis, which has not been previously recognized. 

Prof. PAN Guangjin is the corresponding author of the paper, and Dr. Shan Yongli, PhD candidate Zhang Yanqi and Zhao Yuan are co-first authors of the paper. This work was supported by the Ministry of Science and Technology, the Chinese Academy of Sciences, the National Natural Science Foundation of China, Guangdong Province and Guangzhou City. 

Image by Prof. PAN Guangjin 

The differential requirement of the methylation and de-methylation of H3K27me3 during sequential lineage specification from pluripotency to neural subtypes in human neurogenesis