title: Jmjd3 inhibits reprogramming by upregulating expression of INK4a/Arf and targeting PHF20 for ubiquitination.
abstract: Although somatic cell reprogramming to generate inducible pluripotent stem cells (iPSCs) is associated with profound epigenetic changes, the roles and mechanisms of epigenetic factors in this process remain poorly understood. Here, we identify Jmjd3 as a potent negative regulator of reprogramming. Jmjd3-deficient MEFs produced significantly more iPSC colonies than did wild-type cells, whereas ectopic expression of Jmjd3 markedly inhibited reprogramming. We show that the inhibitory effects of Jmjd3 are produced through both histone demethylase-dependent and -independent pathways. The latter pathway involves Jmjd3 targeting of PHF20 for ubiquitination and degradation via recruitment of an E3 ligase, Trim26. Importantly, PHF20-deficient MEFs could not be converted to fully reprogrammed iPSCs, even with knockdown of Jmjd3, Ink4a, or p21, indicating that PHF20 is required for reprogramming. Our findings demonstrate, to the best of our knowledge, a previously unrecognized role of Jmjd3 in cellular reprogramming and provide molecular insight into the mechanisms by which the Jmjd3-PHF20 axis controls this process.
authors: Center for Inflammation and Epigenetics, The Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors: Wei
authors: W
authors: Zhao
authors: Qingtian
authors: Q
authors: Li
authors: Stephen
authors: S
authors: Ayers
authors: Yifeng
authors: Y
authors: Gu
authors: Zhong
authors: Z
authors: Shi
authors: Qingyuan
authors: Q
authors: Zhu
authors: Yidong
authors: Y
authors: Chen
authors: Helen Y
authors: HY
authors: Wang
authors: Rong-Fu
authors: RF
authors: Wang
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C571905:PHF20 protein, mouse; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; C580663:Trim26 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex