Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration

Abstract

SUMMARY 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 Arid1a loss reprograms chromatin to restrict promoter access by transcription factors such as C/ebpα, which enforces differentiation, and E2F4, which suppresses cell cycle reentry. Thus, epigenetic reprogramming mediated by deletion of a single gene improves mammalian regeneration and suggests strategies to promote tissue repair after injury.

Two possible modes of pioneering associated with combinations of H2A.Z and p300/CBP at nucleosome-occupied enhancers

“…An attractive hypothesis is that NOR-bound sites represent labile/unstable nucleosomes that could hallmark enhancer binding by pioneer TFs. We performed the same analysis with the C/EBPa TF in hepatocytes 19 and found similar results. When examining H2A.Z levels at FoxA2 and C/EBPa sites, we also found more H2A.Z at NORbound sites but unlike for Ets1 and Oct4, only flanking nucleosomes were marked.…”

Epigenetics in liver disease: from biology to therapeutics

“…However, a recent study showed that loss of Arid1a, a component of the chromatin remodelling complexes SWI/SNF, resulted in improved liver regeneration after partial hepatectomy in mice. 82 Conditional overexpression of Arid1a reduced proliferation in wild type (WT) animals after chemical injury. The molecular mechanisms underlying Arid1a-mediated impaired regeneration involve chromatin remodelling, ultimately altering transcriptional access by C/EBPα and E2F4, transcription factors that support terminal differentiation and antagonise proliferation.…”

Switching on regeneration

“…Sun et al (1) (Cell Stem Cell, 2016) recently reported that deleting the Arid1a gene in mice greatly enhances the ability to regenerate the liver and ears after induced injury. Arid1a forms part of SWI/ SNF chromatin-remodeling complexes, which normally support promoter access for transcription factors that promote differentiation and inhibit proliferation.…”

“…Conversely, Arid1a overexpression impaired proliferation and liver regeneration. In addition, inducible whole-body Arid1a deletion is shown to enhance wound healing after ear punching, indicating a more general benefit of Arid1a loss in tissue regeneration (1).…”