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 Ward, Giacomo 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 () and Baoming Qin ()
Additional contact information
Yinghua Huang: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Hui Zhang: Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)
Lulu Wang: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Chuanqing Tang: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Xiaogan Qin: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Xinyu Wu: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Meifang Pan: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Yujia Tang: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Zhongzhou Yang: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Isaac A. Babarinde: Southern University of Science and Technology
Runxia Lin: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Guanyu Ji: E-GENE
Yiwei Lai: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Xueting Xu: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Jianbin Su: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Xue Wen: Jilin University
Takashi Satoh: Osaka University
Tanveer Ahmed: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Vikas Malik: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Carl Ward: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Giacomo Volpe: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Lin Guo: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Jinlong Chen: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Li Sun: Southern University of Science and Technology
Yingying Li: Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)
Xiaofen Huang: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Xichen Bao: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Fei Gao: E-GENE
Baohua Liu: Shenzhen University
Hui Zheng: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Ralf Jauch: The University of Hong Kong
Liangxue Lai: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Guangjin Pan: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Jiekai Chen: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Giuseppe Testa: European Institute of Oncology
Shizuo Akira: Osaka University
Jifan Hu: Jilin University
Duanqing Pei: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Andrew P. Hutchins: Southern University of Science and Technology
Miguel A. Esteban: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS
Baoming Qin: Guangzhou Institutes of Biomedicine and Health (GIBH), CAS

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

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18900-z

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