Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration

• Published in: Cell stem cell 2016-04, Vol.18 (4), p.456-466
• Main Authors: Sun, Xuxu, Chuang, Jen-Chieh, Kanchwala, Mohammed, Wu, Linwei, Celen, Cemre, Li, Lin, Liang, Hanquan, Zhang, Shuyuan, Maples, Thomas, Nguyen, Liem H., Wang, Sam C., Signer, Robert A.J., Sorouri, Mahsa, Nassour, Ibrahim, Liu, Xin, Xu, Jian, Wu, Meng, Zhao, Yong, Kuo, Yi-Chun, Wang, Zhong, Xing, Chao, Zhu, Hao
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation; Cell Proliferation; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Liver - cytology; Liver - metabolism; Liver Regeneration; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2016.03.001

Mammals have partially lost the extensive regenerative capabilities of some vertebrates, possibly as a result of chromatin-remodeling mechanisms that enforce terminal differentiation. Here, we show that deleting the SWI/SNF component Arid1a substantially improves mammalian regeneration. Arid1a expression is suppressed in regenerating tissues, and genetic deletion of Arid1a increases tissue repair following an array of injuries. Arid1a deficiency in the liver increases proliferation, reduces tissue damage and fibrosis, and improves organ function following surgical resection and chemical injuries. Hepatocyte-specific deletion is also sufficient to increase proliferation and regeneration without excessive overgrowth, and global Arid1a disruption potentiates soft tissue healing in the ear. We show that Arid1a loss reprograms chromatin to restrict promoter access by transcription factors such as C/ebpα, which enforces differentiation, and E2F4, which suppresses cell-cycle re-entry. Thus, epigenetic reprogramming mediated by deletion of a single gene improves mammalian regeneration and suggests strategies to promote tissue repair after injury. [Display omitted] •Arid1a loss results in improved regeneration after diverse liver injuries•Arid1a overexpression impairs liver proliferation and regeneration•Arid1a loss also improves tissue repair after ear hole punch•Arid1a loss remodels chromatin, altering transcriptional access by C/EBPα and E2F4 Sun et al. show that deleting Arid1a a SWI/SNF chromatin remodeling complex component, promotes regeneration in the mouse liver and outer ear after surgical and chemical insults. Arid1a loss improves organ function and enhances proliferation after injury by restricting chromatin access of transcription factors that enforce differentiation and repress proliferation.