The cell of origin of colon cancer is typically thought to be the resident somatic stem cells, which are immortal and escape the continual cellular turnover characteristic of the intestinal epithelium. However, recent studies have identified certain conditions in which differentiated cells can acquire stem-like properties and give rise to tumors. Defining the origins of tumors will inform cancer prevention efforts as well as cancer therapies, as cancers with distinct origins often respond differently to treatments. We report here a new condition in which tumors arise from the differentiated intestinal epithelium. Inactivation of the differentiation-promoting transcription factor SMAD4 in the intestinal epithelium was surprisingly well tolerated in the short term. However, after several months, adenomas developed with characteristics of activated WNT signaling. Simultaneous loss of SMAD4 and activation of the WNT pathway led to dedifferentiation and rapid adenoma formation in differentiated tissue. Transcriptional profiling revealed acquisition of stem cell characteristics, and colabeling indicated that cells expressing differentiated enterocyte markers entered the cell cycle and reexpressed stem cell genes upon simultaneous loss of SMAD4 and activation of the WNT pathway. These results indicate that SMAD4 functions to maintain differentiated enterocytes in the presence of oncogenic WNT signaling, thus preventing dedifferentiation and tumor formation in the differentiated intestinal epithelium. This work identifies a mechanism through which differentiated cells prevent tumor formation by suppressing oncogenic plasticity. .
h Transcriptional regulatory mechanisms likely contribute to the etiology of inflammatory bowel disease (IBD), as genetic variants associated with the disease are disproportionately found at regulatory elements. However, the transcription factors regulating colonic inflammation are unclear. To identify these transcription factors, we mapped epigenomic changes in the colonic epithelium upon inflammation. Epigenetic marks at transcriptional regulatory elements responded dynamically to inflammation and indicated a shift in epithelial transcriptional factor networks. Active enhancer chromatin structure at regulatory regions bound by the transcription factor hepatocyte nuclear factor 4␣ (HNF4A) was reduced during colitis. In agreement, upon an inflammatory stimulus, HNF4A was downregulated and showed a reduced ability to bind chromatin. Genetic variants that confer a predisposition to IBD map to HNF4A binding sites in the human colon cell line CaCo2, suggesting impaired HNF4A binding could underlie genetic susceptibility to IBD. Despite reduced HNF4A binding during inflammation, a temporal knockout model revealed HNF4A still actively protects against inflammatory phenotypes and promotes immune regulatory gene expression in the inflamed colonic epithelium. These findings highlight the potential for HNF4A agonists as IBD therapeutics.T he colonic epithelium is an integral component in inflammatory bowel disease (IBD) pathology, as compromised epithelial integrity permits increased interaction between the gut immune system and luminal antigens. However, the colonic epithelium is not merely a passive barrier against luminal microbes; active epithelial roles include antigen presentation, adaptive and innate immune regulation, and antimicrobial peptide production, among others (1-3). A detailed molecular understanding of the epithelium's role in IBD and how the epithelium responds to an inflammatory insult could offer therapeutic alternatives or innovations to current treatments.Transcriptional regulatory networks serve as the interface between the extracellular environment and genome regulation. Defining how the regulatory networks of the epithelium respond to inflammation could provide important insights into the role of the epithelium in IBD. Transcriptional regulatory networks can be inferred from a cell's epigenome, which is a collection of epigenomic marks, typically a histone posttranslational modification that is associated with a particular genome function. Transcriptional enhancer epigenomic marks are strong predictors of cellular identity and gene expression (4, 5). Nucleosomes containing histone 3, lysine 27 acetylation (H3K27ac) can be used to identify regions that have distal regulatory activity (transcriptional enhancers), flank chromatin-accessible transcription factor binding regions, and are predictive of active transcription in a conditionspecific manner (4, 6, 7). Changes in H3K27ac levels and DNA accessibility predict changes in transcription factor occupancy (8, 9); dynamic enhancer chromatin structur...
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