Engineering mouse cell fate controller by rational design

Tao Huang, Dong Liu, Xiaomin Wang, Junqi Kuang, Manqi Wu, Beibei Wang, Zechuan Liang, Yixin Fan, Bo Chen, Zhaoyi Ma, Yu Fu, Wenhui Zhang, Jin Ming, Yue Qin, Chengchen Zhao (), Bo Wang () and Duanqing Pei ()
Additional contact information
Tao Huang: Zhejiang University
Dong Liu: Westlake University
Xiaomin Wang: Westlake University
Junqi Kuang: Westlake University
Manqi Wu: Westlake University
Beibei Wang: Westlake University
Zechuan Liang: Zhejiang University
Yixin Fan: Chinese Academy of Sciences
Bo Chen: Westlake University
Zhaoyi Ma: Zhejiang University
Yu Fu: Westlake University
Wenhui Zhang: Zhejiang University
Jin Ming: Westlake University
Yue Qin: Westlake University
Chengchen Zhao: Westlake University
Bo Wang: Westlake University
Duanqing Pei: Westlake University

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Cell fate is likely regulated by a common machinery, while components of this machine remain to be identified. Here we report the design and testing of engineered cell fate controller NanogBiD, fusing BiD or BRG1 interacting domain of SS18 with Nanog. NanogBiD promotes mouse somatic cell reprogramming efficiently in contrast to the ineffective native protein under multiple testing conditions. Mechanistic studies further reveal that it facilitates cell fate transition by recruiting the intended Brg/Brahma-associated factor (BAF) complex to modulate chromatin accessibility and reorganize cell state specific enhancers known to be occupied by canonical Nanog, resulting in precocious activation of multiple genes including Sall4, miR-302, Dppa5a and Sox15 towards pluripotency. Although we have yet to test our approach in other species, our findings suggest that engineered chromatin regulators may provide much needed tools to engineer cell fate in the cells as drugs era.

Date: 2024
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DOI: 10.1038/s41467-024-50551-2

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