標題: | Ash2l interacts with Oct4-stemness circuitry to promote super-enhancer-driven pluripotency network |
作者: | Tsai, Ping-Hsing Chien, Yueh Wang, Mong-Lien Hsu, Chih-Hung Laurent, Benoit Chou, Shih-Jie Chang, Wei-Chao Chien, Chian-Shiu Li, Hsin-Yang Lee, Hsin-Chen Huo, Teh-Ia Hung, Jui-Hung Chen, Chung-Hsuan Chiou, Shih-Hwa 交大名義發表 資訊工程學系 National Chiao Tung University Department of Computer Science |
公開日期: | 4-Nov-2019 |
摘要: | 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. |
URI: | http://dx.doi.org/10.1093/nar/gkz801 http://hdl.handle.net/11536/153149 |
ISSN: | 0305-1048 |
DOI: | 10.1093/nar/gkz801 |
期刊: | NUCLEIC ACIDS RESEARCH |
Volume: | 47 |
Issue: | 19 |
起始頁: | 10115 |
結束頁: | 10133 |
Appears in Collections: | Articles |