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. 2022 Jan 1;36(1-2):38–52. doi: 10.1101/gad.348983.121

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© 2022 Singh et al.; Published by Cold Spring Harbor Laboratory Press

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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Figure 1. — Intestinal TFs induce an intestinal program in mouse stomach organoids. (A) Immunoblots of forced GFP (control), HNF4A, or CDX2 expression in gastric organoids. Each lane represents a distinct organoid line. (B) Expression of intestinal genes representing goblet, enterocyte, enteroendocrine, and Paneth cells in stomach organoids that express GFP, HNF4A, or CDX2, and in intestinal organoids (INT). A table of normalized RNA-seq counts from each organoid line shows CDX2 and HNF4A overexpression and up-regulation of canonical intestinal transcripts. (C, top) Bright-field microscopy of representative stomach organoids, including some with buds that resemble intestinal crypt-like outpouchings. (Bottom) Histochemistry (lysozyme and Muc2 immunostain and alkaline phosphatase) showing intestinal features. (D) Two independent human BE data sets (di Pietro et al. 2012; Owen et al. 2018) show that genes responsive to CDX2 in mouse stomach organoids are up-regulated in BE compared with native stomach epithelium. (E) Gene set enrichment analysis (GSEA) of 400 genes induced in CDX2⁺ gastric organoids (log₂ fold increase >1, q < 0.05, DESeq2), showing resemblance to human BE (data from clinical samples) (Owen et al. 2018). (NES) Normalized enrichment score, (FDR) false discovery rate. (F) Enhancers with increased chromatin access (log₂ fold change >1, q < 0.05, DESeq2) in CDX2⁺ and HNF4A⁺ stomach organoids overlap significantly with sites selectively accessible in intestinal compared with stomach organoids. Representation factors 7344 (CDX2) and 7748 (HNF4A); P = 0. Motifs for intestinal TFs are highly enriched at enhancers rendered accessible in the presence of CDX2.