BRG1 attenuates colonic inflammation and tumorigenesis through autophagy-dependent oxidative stress sequestration

Min Liu,Da Fu,Wei-Qiang Gao,Li Li,Wei Li,Ni Li,Junjie Peng,Tongyu Sun

doi:10.1038/s41467-019-12573-z

Abstract

Autophagy is a central component of integrated stress responses that influences many inflammatory diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). While the core machinery is known, the molecular basis of the epigenetic regulation of autophagy and its role in colon inflammation remain largely undefined. Here, we report that BRG1, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is required for the homeostatic maintenance of intestinal epithelial cells (IECs) to prevent the inflammation and tumorigenesis. BRG1 emerges as a key regulator that directly governs the transcription of Atg16l1, Ambra1, Atg7 and Wipi2, which are important for autophagosome biogenesis. Defective autophagy in BRG1-deficient IECs results in excess reactive oxygen species (ROS), which leads to the defects in barrier integrity. Together, our results establish that BRG1 may represent an autophagy checkpoint that is pathogenetically linked to colitis and is therefore likely a potential therapeutic target for disease intervention.

Highlights

Autophagy is a central component of integrated stress responses that influences many inflammatory diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC)
Consistent with the previous reports, analyses of public datasets suggested that BRG1 mRNA was reduced in IBD specimens as compared with those in healthy controls
Compared with the levels in biopsies from healthy specimens, we showed that BRG1 mRNA levels were markedly decreased in the IBD biopsies (Fig. 1b)

Summary

Introduction

Autophagy is a central component of integrated stress responses that influences many inflammatory diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). We report that BRG1, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is required for the homeostatic maintenance of intestinal epithelial cells (IECs) to prevent the inflammation and tumorigenesis. The defects in maintaining the homeostasis of intestinal epithelial cells (IECs) are known to trigger chronic inflammation and repair, which occasionally results in dysplasia[6,7,8]. The insufficient autophagy results in the accumulation of undesirable components that fuel inflammation, stimulate ROS, trigger cell death, and induce genomic instability, all of which cause the formation of the hallmarks of cancer[10,13,14]. Experiments using genetically engineered mouse models (GEMs) indicate that autophagy dysfunctions, such as ablation of Atg16l1, Atg[5], or

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