JMJD3 acts in tandem with KLF4 to facilitate reprogramming to pluripotency

Yinghua Huang, Hui Zhang, Lulu Wang, Chuanqing Tang, Xiaogan Qin, Xinyu Wu, Meifang Pan, Yujia Tang, Zhongzhou Yang, Isaac A. Babarinde, Runxia Lin, Guanyu Ji, Yiwei Lai, Xueting Xu, Jianbin Su, Xue Wen, Takashi Satoh, Tanveer Ahmed, Vikas Malik, Carl WardGiacomo Volpe, Lin Guo, Jinlong Chen, Li Sun, Yingying Li, Xiaofen Huang, Xichen Bao, Fei Gao, Baohua Liu, Hui Zheng, Ralf Jauch, Liangxue Lai, Guangjin Pan, Jiekai Chen, Giuseppe Testa, Shizuo Akira, Jifan Hu, Duanqing Pei, Andrew P. Hutchins, Miguel A. Esteban, Baoming Qin

Research output: Contribution to journalArticlepeer-review

Abstract

The interplay between the Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) and transcriptional/epigenetic co-regulators in somatic cell reprogramming is incompletely understood. Here, we demonstrate that the histone H3 lysine 27 trimethylation (H3K27me3) demethylase JMJD3 plays conflicting roles in mouse reprogramming. On one side, JMJD3 induces the pro-senescence factor Ink4a and degrades the pluripotency regulator PHF20 in a reprogramming factor-independent manner. On the other side, JMJD3 is specifically recruited by KLF4 to reduce H3K27me3 at both enhancers and promoters of epithelial and pluripotency genes. JMJD3 also promotes enhancer-promoter looping through the cohesin loading factor NIPBL and ultimately transcriptional elongation. This competition of forces can be shifted towards improved reprogramming by using early passage fibroblasts or boosting JMJD3’s catalytic activity with vitamin C. Our work, thus, establishes a multifaceted role for JMJD3, placing it as a key partner of KLF4 and a scaffold that assists chromatin interactions and activates gene transcription.

Original languageEnglish
Article number5061
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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