Disruption of OCT4 Ubiquitination Increases OCT4 Protein Stability and ASH2L-B-Mediated H3K4 Methylation Promoting Pluripotency Acquisition

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2018 Oct 2

PMID 30269953

Citations 12

Authors

Shuang Li

Feng Xiao

Junmei Zhang

Xiaozhi Sun

Han Wang

Yanwu Zeng

Jing Hu

Fan Tang

Junjie Gu

Yingming Zhao

Ying Jin

Bing Liao

Affiliations

Soon will be listed here.

Abstract

The protein level of OCT4, a core pluripotency transcription factor, is vital for embryonic stem cell (ESC) maintenance, differentiation, and somatic cell reprogramming. However, how OCT4 protein levels are controlled during reprogramming remains largely unknown. Here, we identify ubiquitin conjugation sites of OCT4 and report that disruption of WWP2-catalyzed OCT4 ubiquitination or ablation of Wwp2 significantly promotes the efficiency of pluripotency induction from mouse embryonic fibroblasts. Mechanistically, disruption of WWP2-mediated OCT4 ubiquitination elevates OCT4 protein stability and H3K4 methylation level during the reprogramming process. Furthermore, we reveal that OCT4 directly activates expression of Ash2l-b, and that ASH2L-B is a major isoform of ASH2L highly expressed in ESCs and required for somatic cell reprogramming. Together, this study emphasizes the importance of ubiquitination manipulation of the reprogramming factor and its interplay with the epigenetic regulator for successful reprogramming, opening a new avenue to improve the efficiency of pluripotency induction.

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References

Liu L, Michowski W, Inuzuka H, Shimizu K, Nihira N, Chick J . G1 cyclins link proliferation, pluripotency and differentiation of embryonic stem cells. Nat Cell Biol. 2017; 19(3):177-188. PMC: 5489757. DOI: 10.1038/ncb3474. View

Jang H, Kim T, Yoon S, Choi S, Kang T, Kim S . O-GlcNAc regulates pluripotency and reprogramming by directly acting on core components of the pluripotency network. Cell Stem Cell. 2012; 11(1):62-74. DOI: 10.1016/j.stem.2012.03.001. View

Wei F, Scholer H, Atchison M . Sumoylation of Oct4 enhances its stability, DNA binding, and transactivation. J Biol Chem. 2007; 282(29):21551-60. DOI: 10.1074/jbc.M611041200. View

Koche R, Smith Z, Adli M, Gu H, Ku M, Gnirke A . Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell. 2011; 8(1):96-105. PMC: 3220622. DOI: 10.1016/j.stem.2010.12.001. View

Zhang Z, Liao B, Xu M, Jin Y . Post-translational modification of POU domain transcription factor Oct-4 by SUMO-1. FASEB J. 2007; 21(12):3042-51. DOI: 10.1096/fj.06-6914com. View

Ang Y, Tsai S, Lee D, Monk J, Su J, Ratnakumar K . Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell. 2011; 145(2):183-97. PMC: 3097468. DOI: 10.1016/j.cell.2011.03.003. View

Thomson J, Itskovitz-Eldor J, Shapiro S, Waknitz M, Swiergiel J, Marshall V . Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282(5391):1145-7. DOI: 10.1126/science.282.5391.1145. View

Wan M, Liang J, Xiong Y, Shi F, Zhang Y, Lu W . The trithorax group protein Ash2l is essential for pluripotency and maintaining open chromatin in embryonic stem cells. J Biol Chem. 2012; 288(7):5039-48. PMC: 3576105. DOI: 10.1074/jbc.M112.424515. View

Evans M, Kaufman M . Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981; 292(5819):154-6. DOI: 10.1038/292154a0. View

10.

Karwacki-Neisius V, Goke J, Osorno R, Halbritter F, Ng J, Weisse A . Reduced Oct4 expression directs a robust pluripotent state with distinct signaling activity and increased enhancer occupancy by Oct4 and Nanog. Cell Stem Cell. 2013; 12(5):531-45. PMC: 3650585. DOI: 10.1016/j.stem.2013.04.023. View

11.

Xu H, Liao B, Zhang Q, Wang B, Li H, Zhong X . Wwp2, an E3 ubiquitin ligase that targets transcription factor Oct-4 for ubiquitination. J Biol Chem. 2004; 279(22):23495-503. DOI: 10.1074/jbc.M400516200. View

12.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

13.

Maddika S, Kavela S, Rani N, Palicharla V, Pokorny J, Sarkaria J . WWP2 is an E3 ubiquitin ligase for PTEN. Nat Cell Biol. 2011; 13(6):728-33. PMC: 3926303. DOI: 10.1038/ncb2240. View

14.

Dou Y, Hess J . Mechanisms of transcriptional regulation by MLL and its disruption in acute leukemia. Int J Hematol. 2008; 87(1):10-8. DOI: 10.1007/s12185-007-0009-8. View

15.

Saxe J, Tomilin A, Scholer H, Plath K, Huang J . Post-translational regulation of Oct4 transcriptional activity. PLoS One. 2009; 4(2):e4467. PMC: 2637973. DOI: 10.1371/journal.pone.0004467. View

16.

Niwa H, Miyazaki J, Smith A . Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet. 2000; 24(4):372-6. DOI: 10.1038/74199. View

17.

Yang Z, Augustin J, Hu J, Jiang H . Physical Interactions and Functional Coordination between the Core Subunits of Set1/Mll Complexes and the Reprogramming Factors. PLoS One. 2015; 10(12):e0145336. PMC: 4686221. DOI: 10.1371/journal.pone.0145336. View

18.

Szabo P, Hubner K, Scholer H, Mann J . Allele-specific expression of imprinted genes in mouse migratory primordial germ cells. Mech Dev. 2002; 115(1-2):157-60. DOI: 10.1016/s0925-4773(02)00087-4. View

19.

Buckley S, Aranda-Orgilles B, Strikoudis A, Apostolou E, Loizou E, Moran-Crusio K . Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system. Cell Stem Cell. 2012; 11(6):783-98. PMC: 3549668. DOI: 10.1016/j.stem.2012.09.011. View

20.

Steward M, Lee J, ODonovan A, Wyatt M, Bernstein B, Shilatifard A . Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nat Struct Mol Biol. 2006; 13(9):852-4. DOI: 10.1038/nsmb1131. View