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

Author:

Tsai Ping-Hsing12,Chien Yueh12,Wang Mong-Lien1345,Hsu Chih-Hung6,Laurent Benoit7,Chou Shih-Jie125,Chang Wei-Chao8,Chien Chian-Shiu12,Li Hsin-Yang59,Lee Hsin-Chen25,Huo Teh-Ia210,Hung Jui-Hung11,Chen Chung-Hsuan12,Chiou Shih-Hwa123512ORCID

Affiliation:

1. Department of Medical Research, Taipei VeteransGeneral Hospital, Taipei 11217, Taiwan

2. Institute of Pharmacology, National Yang-Ming University, Taipei 11221, Taiwan

3. Institute of Food Safety and Health Risk Assessment, National Yang-Ming University, Taipei 11221, Taiwan

4. Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan

5. School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan

6. Department of Public Health, and Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China

7. Boston Children’s Hospital and Harvard Medical School, Boston MA 02115, USA

8. Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan

9. Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 11217, Taiwan

10. Section of Gastroenterology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan

11. Institutes of Data Science and Engineering, and Department of computer science, National Chiao-Tung University, Hsinchu 30010, Taiwan

12. Genomic Research Center, Academia Sinica, Taipei 11529, Taiwan

Abstract

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.

Funder

Ministry of Science and Technology

Academia Sinica

Taipei Veterans General Hospital

Department of Health Cancer Center Research of Excellence

NRPB Human iPSC Alliance-Core Service

VGH, TSGH, NDMC, AS Joint Research Program

National Health Research Institutes

Center for Intelligent Drug Systems and Smart Bio-devices

Ministry of Education

Publisher

Oxford University Press (OUP)

Subject

Genetics

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