Poly(ADP-ribose) polymerase 1 regulates nuclear reprogramming and promotes iPSC generation without c-Myc

Shih Hwa Chiou*, Bo Hwa Jiang, Yung Luen Yu, Shih Jie Chou, Ping Hsing Tsai, Wei Chao Chang, Liang Kung Chen, Li Hsin Chen, Yueh Chien, Guang-Yuh Chiou

*Corresponding author for this work

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Poly(ADP-ribose) polymerase 1 (Parp1) catalyzes poly(ADP-ribosylation) (PARylation) and induces replication networks involved in multiple nuclear events. Using mass spectrometry and Western blotting, Parp1 and PARylation activity were intensively detected in induced pluripotent stem cells (iPSCs) and embryonic stem cells, but they were lower in mouse embryonic fibroblasts (MEFs) and differentiated cells. We show that knockdown of Parp1 and pharmacological inhibition of PARylation both reduced the efficiency of iPSC generation induced by Oct4/Sox2/Klf4/c-Myc. Furthermore, Parp1 is able to replace Klf4 or c-Myc to enhance the efficiency of iPSC generation. In addition, mouse iPSCs generated from Oct4/Sox2/Parp1-overexpressing MEFs formed chimeric offspring. Notably, the endogenous Parp1 and PARylation activity was enhanced by overexpression of c-Myc and repressed by c-Myc knockdown. A chromatin immunoprecipitation assay revealed a direct interaction of c-Myc with the Parp1promoter. PAR-resin pulldown, followed by proteomic analysis, demonstrated high levels of PARylated Chd1L, DNA ligase III, SSrp1, Xrcc-6/Ku70, and Parp2 in pluripotent cells, which decreased during the differentiation process. These data show that the activation of Parp1, partly regulated by endogenous c-Myc, effectively promotes iPSC production and helps to maintain a pluripotent state by posttranslationally modulating protein PARylation.

Original languageEnglish
Pages (from-to)85-98
Number of pages14
JournalJournal of Experimental Medicine
Volume210
Issue number1
DOIs
StatePublished - 1 Jan 2013

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    Chiou, S. H., Jiang, B. H., Yu, Y. L., Chou, S. J., Tsai, P. H., Chang, W. C., Chen, L. K., Chen, L. H., Chien, Y., & Chiou, G-Y. (2013). Poly(ADP-ribose) polymerase 1 regulates nuclear reprogramming and promotes iPSC generation without c-Myc. Journal of Experimental Medicine, 210(1), 85-98. https://doi.org/10.1084/jem.20121044