TY - JOUR
T1 - Jmjd3 inhibits reprogramming by upregulating expression of INK4a/Arf and targeting PHF20 for ubiquitination
AU - Zhao, Wei
AU - Li, Qingtian
AU - Ayers, Stephen
AU - Gu, Yifeng
AU - Shi, Zhong
AU - Zhu, Qingyuan
AU - Chen, Yidong
AU - Wang, Helen Y.
AU - Wang, Rong Fu
N1 - Funding Information:
We would like to thank Dr. Yi Li at Baylor College of Medicine for providing Tet-O-Myc transgenic mice, Dr. Mark Bedford at M.D. Anderson Cancer Center for PHF20 KO mice, Dr. Dan Liu at Baylor College of Medicine for assistance with shRNA screening, and Dr. Paul Webb for assistance in ChIP-seq experiments. We would also like to thank John Gilbert and Adebusola A. Ajibade for their critical reading of this manuscript. This work was in part supported by grants from National Cancer Institute, NIH (R01CA09327, R01CA101795, R01CA116408, R01CA121191, and R01 DA030338), and Cancer Prevention and Research Institute of Texas (RP121048) to R.-F.W. and from The Methodist Hospital Research Institute.
PY - 2013/2/28
Y1 - 2013/2/28
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2013.02.006
DO - 10.1016/j.cell.2013.02.006
M3 - Article
C2 - 23452852
AN - SCOPUS:84874789264
SN - 0092-8674
VL - 152
SP - 1037
EP - 1050
JO - Cell
JF - Cell
IS - 5
ER -