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Cell Stem Cell. 2016 Apr 7;18(4):456-66. doi: 10.1016/j.stem.2016.03.001. Epub 2016 Mar 24.

Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration.

Author information

1
Departments of Pediatrics and Internal Medicine, Children's Research Institute, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2
Bioinformatics Core, Eugene McDermott Center for Human Growth & Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Departments of Pediatrics and Internal Medicine, Children's Research Institute, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Organ Transplant Center, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
4
Departments of Pediatrics and Internal Medicine, Children's Research Institute, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
5
Departments of Pediatrics and Internal Medicine, Children's Research Institute, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6
Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
7
Mindich Child Health and Development Institute and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8
Departments of Pharmacology and Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
9
Department of Cardiac Surgery, Cardiovascular Research Center, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.
10
Departments of Pediatrics and Internal Medicine, Children's Research Institute, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: hao.zhu@utsouthwestern.edu.

Abstract

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.

Comment in

PMID:
27044474
PMCID:
PMC4826298
DOI:
10.1016/j.stem.2016.03.001
[Indexed for MEDLINE]
Free PMC Article

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