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Post-translational modification of POU domain transcription factor Oct-4 by SUMO-1

Zhihong Zhang^*,, Bing Liao^*,, Ming Xu^*, and Ying Jin^*,,,1

^* Institute of Health Sciences and Institute of Stem Cell Research, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;

Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai JiaoTong University School of Medicine, Shanghai, China; and

Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai China

¹Correspondence: Institute of Health Sciences, 225 South Chongqing Rd., Shanghai, China 200025. E-mail: yjin{at}sibs.ac.cn

POU domain transcription factor Oct-4 plays a crucial role in maintaining self-renewal and pluripotency of embryonic stem (ES) cells in a concentration-dependent manner. However, the molecular mechanism controlling Oct-4 levels in ES cells remains largely unknown. To explore the molecular mechanism regulating Oct-4 function, we constructed a mouse ES cell cDNA library and performed yeast two-hybrid screening using the POU domain of Oct-4 as bait. Here, we present novel evidence for Oct-4 interaction with Ubc9, an E2 conjugation enzyme for SUMO modification, and its modification by SUMO-1. The SUMO acceptor site was identified at lysine residue 118. Importantly, disruption of Oct-4 sumoylation reduced Oct-4 protein stability and self-renewal capacity in ES cells. Interestingly, expression of cYes was found to reduce when Oct-4 sumoylation was disrupted or Oct-4 expression downregulated in ES cells. We further demonstrate that Oct-4 was recruited to the cYes promoter region, suggesting that cYes might be a novel downstream gene of Oct-4. Taken together, we first demonstrate the post-translational modification of endogenous Oct-4 by SUMO and the role of sumoylation in regulating Oct-4 protein stability and function. Our findings provide new evidence for the important role of post-translational modification in controlling Oct-4 function in ES cells.—Zhang, Z., Liao, B., Xu, M., Jin, Y. Post-translational modification of POU domain transcription factor Oct-4 by SUMO-1.

Key Words: embryonic stem cells • sumoylation • protein stability • cYes