Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium
José B. Sáenz, Nancy Vargas, Charles J. Cho, Jason C. Mills
José B. Sáenz, Nancy Vargas, Charles J. Cho, Jason C. Mills
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Research Article Cell biology Gastroenterology

Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium

Abstract

Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of gastric metaplasia. Mouse organoid and in vivo genetic models showed that ADAR1 coordinated a cell-intrinsic, epithelium-autonomous, and interferon signaling–independent dsRNA response. In addition, dsRNA accumulated within a differentiated epithelial population (chief cells) in mouse and human stomachs as these cells reprogrammed to a proliferative, reparative (metaplastic) state. Finally, chief cells required ADAR1 to reenter the cell cycle during metaplasia. Thus, cell-intrinsic ADAR1 signaling is critical for the induction of metaplasia. Because metaplasia increases cancer risk, these findings support roles for ADAR1 and the response to dsRNA in oncogenesis.

Authors

José B. Sáenz, Nancy Vargas, Charles J. Cho, Jason C. Mills

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Figure 2

The dsRNA response is upregulated during gastric metaplasia.

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The dsRNA response is upregulated during gastric metaplasia. (A) Gene ex...
(A) Gene expression profiling of gastric corpus tissue from wild-type mice treated with either vehicle (green) or HD-Tam for 48 hours (purple), or infected with H. pylori for 6.5 months (yellow). The hatched area is magnified in the right panel, with expression changes for the corresponding genes. (B) Genes highlighted in yellow showed higher relative expression following H. pylori infection, while genes highlighted in purple showed relatively higher expression following HD-Tam treatment. Genes pertaining to the dsRNA response are in black. Genes in yellow and purple have not been shown to be involved in the dsRNA response. Dotted lines represent 2-fold cutoffs. (C and D) The dsRNA response is activated at the transcriptional (left panels) and protein (right panels) levels following either HD-Tam treatment (C) or chronic H. pylori infection (D). For left panels, each data point represents gastric corpus tissue from an individual mouse. Fold expression changes were determined by quantitative reverse transcription PCR (qRT-PCR) and are relative to vehicle-treated (C) or mock-infected mice (D). The dotted line represents the average expression in vehicle-treated or mock-infected mice. For C, pooled data from 3 consecutive, independent experiments are shown. For C, “V” corresponds to vehicle treatment. For D, each data point represents an individual mouse infected with H. pylori for 3 months (unfilled circles), 6.5 months (half-filled circles), or 11 months (filled circles). Each lane of the Western blots represents gastric corpus tissue of a mouse from a representative experiment under each experimental treatment condition. For left panels, P values were determined using 2-tailed Student’s t test, where *, P < 0.05; **, P < 0.01; ***, P < 0.001. HD-Tam, high-dose tamoxifen; Hp, Helicobacter pylori.