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.

JMJD3 acts in tandem with KLF4 to facilitate reprogramming to pluripotency / Y. Huang, H. Zhang, L. Wang, C. Tang, X. Qin, X. Wu, M. Pan, Y. Tang, Z. Yang, I.A. Babarinde, R. Lin, G. Ji, Y. Lai, X. Xu, J. Su, X. Wen, T. Satoh, T. Ahmed, V. Malik, C. Ward, G. Volpe, L. Guo, J. Chen, L. Sun, Y. Li, X. Huang, X. Bao, F. Gao, B. Liu, H. Zheng, R. Jauch, L. Lai, G. Pan, J. Chen, G. Testa, S. Akira, J. Hu, D. Pei, A.P. Hutchins, M.A. Esteban, B. Qin. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 11:1(2020), pp. 5061.1-5061.16. [10.1038/s41467-020-18900-z]

JMJD3 acts in tandem with KLF4 to facilitate reprogramming to pluripotency

G. Testa;
2020

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.
Animals; Catalysis; Cell Proliferation; Cellular Senescence; Demethylation; Enhancer Elements, Genetic; Epithelial Cells; Fibroblasts; Gene Expression Regulation, Developmental; Genome; Histones; Jumonji Domain-Containing Histone Demethylases; Kruppel-Like Transcription Factors; Lysine; Mice; Models, Biological; Pluripotent Stem Cells; Promoter Regions, Genetic; Transcriptional Activation; Cellular Reprogramming
Settore BIO/11 - Biologia Molecolare
Settore BIO/13 - Biologia Applicata
Settore BIO/10 - Biochimica
2020
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/802233
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