Ash2l interacts with Oct4-stemness circuitry to promote super-enhancer-driven pluripotency network

Ping Hsing Tsai, Yueh Chien, Mong Lien Wang, Chih Hung Hsu, Benoit Laurent, Shih Jie Chou, Wei Chao Chang, Chian Shiu Chien, Hsin Yang Li, Hsin Chen Lee, Teh Ia Huo, Jui Hung Hung, Chung Hsuan Chen, Shih Hwa Chiou

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Pluripotency and cell fates can be modulated through the regulation of super-enhancers; however, the underlying mechanisms are unclear. Here, we showed a novel mechanism in which Ash2l directly binds to super-enhancers of several stemness genes to regulate pluripotency and self-renewal in pluripotent stem cells. Ash2l recruits Oct4/Sox2/Nanog (OSN) to form Ash2l/OSN complex at the super-enhancers of Jarid2, Nanog, Sox2 and Oct4, and further drives enhancer activation, upregulation of stemness genes, and maintains the pluripotent circuitry. Ash2l knockdown abrogates the OSN recruitment to all super-enhancers and further hinders the enhancer activation. In addition, CRISPRi/dCas9-mediated blocking of Ash2l-binding motifs at these super-enhancers also prevents OSN recruitment and enhancer activation, validating that Ash2l directly binds to super-enhancers and initiates the pluripotency network. Transfection of Ash2l with W118A mutation to disrupt Ash2l-Oct4 interaction fails to rescue Ash2l-driven enhancer activation and pluripotent gene upregulation in Ash2l-depleted pluripotent stem cells. Together, our data demonstrated Ash2l formed an enhancer-bound Ash2l/OSN complex that can drive enhancer activation, govern pluripotency network and stemness circuitry.

Original languageEnglish
Pages (from-to)10115-10133
Number of pages19
JournalNucleic acids research
Volume47
Issue number19
DOIs
StatePublished - 4 Nov 2019

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    Tsai, P. H., Chien, Y., Wang, M. L., Hsu, C. H., Laurent, B., Chou, S. J., Chang, W. C., Chien, C. S., Li, H. Y., Lee, H. C., Huo, T. I., Hung, J. H., Chen, C. H., & Chiou, S. H. (2019). Ash2l interacts with Oct4-stemness circuitry to promote super-enhancer-driven pluripotency network. Nucleic acids research, 47(19), 10115-10133. https://doi.org/10.1093/nar/gkz801