Transcription factor-mediated intestinal metaplasia and the role of a shadow enhancer

Barrett's esophagus (BE) and gastric intestinal metaplasia are related premalignant conditions in which areas of human stomach epithelium express mixed gastric and intestinal features. Intestinal transcription factors (TFs) are expressed in both conditions, with unclear causal roles and cis-regulatory mechanisms. Ectopic CDX2 reprogrammed isogenic mouse stomach organoid lines to a hybrid stomach–intestinal state transcriptionally similar to clinical metaplasia; squamous esophageal organoids resisted this CDX2-mediated effect. Reprogramming was associated with induced activity at thousands of previously inaccessible intestine-restricted enhancers, where CDX2 occupied DNA directly. HNF4A, a TF recently implicated in BE pathogenesis, induced weaker intestinalization by binding a novel shadow Cdx2 enhancer and hence activating Cdx2 expression. CRISPR/Cas9-mediated germline deletion of that cis-element demonstrated its requirement in Cdx2 induction and in the resulting activation of intestinal genes in stomach cells. dCas9-conjugated KRAB repression mapped this activity to the shadow enhancer's HNF4A binding site. Altogether, we show extensive but selective recruitment of intestinal enhancers by CDX2 in gastric cells and that HNF4A-mediated ectopic CDX2 expression in the stomach occurs through a conserved shadow cis-element. These findings identify mechanisms for TF-driven intestinal metaplasia and a likely pathogenic TF hierarchy.

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CDX2 expression is progressively decreased in human gastric intestinal metaplasia, dysplasia and cancer

Modern Pathology ◽

10.1038/modpathol.3800968 ◽

2007 ◽

Vol 20 (12) ◽

pp. 1286-1297 ◽

Cited By ~ 56

Author(s):

Qiang Liu ◽

Ming Teh ◽

Kosei Ito ◽

Nilesh Shah ◽

Yoshiaki Ito ◽

...

Keyword(s):

Intestinal Metaplasia ◽

Gastric Intestinal Metaplasia ◽

Cdx2 Expression

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Potential role of aquaporin 3 in gastric intestinal metaplasia

Oncotarget ◽

10.18632/oncotarget.5370 ◽

2015 ◽

Vol 6 (36) ◽

pp. 38926-38933 ◽

Cited By ~ 4

Author(s):

Haijian Zhao ◽

Xiaojun Yang ◽

Yangchun Zhou ◽

Weiming Zhang ◽

Yao Wang ◽

...

Keyword(s):

Intestinal Metaplasia ◽

Potential Role ◽

Aquaporin 3 ◽

Gastric Intestinal Metaplasia

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MicroRNA-92a-1–5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia

Gut ◽

10.1136/gutjnl-2017-315318 ◽

2019 ◽

Vol 68 (10) ◽

pp. 1751-1763 ◽

Cited By ~ 9

Author(s):

Ting Li ◽

Hanqing Guo ◽

Hong Li ◽

Yanzhi Jiang ◽

Kun Zhuang ◽

...

Keyword(s):

Intestinal Metaplasia ◽

Bile Acids ◽

Messenger Rna ◽

Tissue Microarrays ◽

Chronic Atrophic Gastritis ◽

Gastric Epithelium ◽

Gastric Intestinal Metaplasia ◽

Gastric Cells ◽

Regulatory Circuits ◽

Gastric Cancer Cell Lines

Background and aimsGastric intestinal metaplasia (IM) is common in the gastric epithelium of patients with chronic atrophic gastritis. CDX2 activation in IM is driven by reflux of bile acids and following chronic inflammation. But the mechanism underlying how bile acids activate CDX2 in gastric epithelium has not been fully explored.MethodsWe performed microRNA (miRNA) and messenger RNA (mRNA) profiling using microarray in cells treated with bile acids. Data integration of the miRNA/mRNA profiles with gene ontology (GO) analysis and bioinformatics was performed to detect potential miRNA-mRNA regulatory circuits. Transfection of gastric cancer cell lines with miRNA mimics and inhibitors was used to evaluate their effects on the expression of candidate targets and functions. Immunohistochemistry and in situhybridisation were used to detect the expression of selected miRNAs and their targets in IM tissue microarrays.ResultsWe demonstrate a bile acids-triggered pathway involving upregulation of miR-92a-1–5p and suppression of its target FOXD1 in gastric cells. We first found that miR-92a-1–5p was increased in IM tissues and induced by bile acids. Moreover, miR-92a-1–5p was found to activate CDX2 and downstream intestinal markers by targeting FOXD1/FOXJ1 axis and modulating activation of nuclear factor kappa B (NF-κB) pathway. Furthermore, these effects were found to be clinical relevant, as high miR-92a-1–5p levels were correlated with low FOXD1 levels and high CDX2 levels in IM tissues.ConclusionThese findings suggest a miR-92a-1–5p/FOXD1/NF-κB/CDX2 regulatory axis plays key roles in the generation of IM phenotype from gastric cells. Suppression of miR-92a-1–5p and restoration of FOXD1 may be a preventive approach for gastric IM in patients with bile regurgitation.

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Role of digital chromoendoscopy and confocal laser endomicroscopy for gastric intestinal metaplasia and cancer surveillance

World Journal of Gastrointestinal Endoscopy ◽

10.4253/wjge.v4.i10.472 ◽

2012 ◽

Vol 4 (10) ◽

pp. 472 ◽

Cited By ~ 8

Author(s):

Rapat Pittayanon

Keyword(s):

Intestinal Metaplasia ◽

Cancer Surveillance ◽

Confocal Laser Endomicroscopy ◽

Confocal Laser ◽

Gastric Intestinal Metaplasia

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Endoscopic grading of gastric intestinal metaplasia on risk assessment for early gastric neoplasia: can we replace histology assessment also in the West?

Gut ◽

10.1136/gutjnl-2019-320091 ◽

2020 ◽

Vol 69 (10) ◽

pp. 1762-1768 ◽

Cited By ~ 3

Author(s):

Pedro Marcos ◽

Gisela Brito-Gonçalves ◽

Diogo Libânio ◽

Inês Pita ◽

Rui Castro ◽

...

Keyword(s):

Risk Stratification ◽

Intestinal Metaplasia ◽

Matched Control ◽

Gastric Intestinal Metaplasia ◽

Control Subjects ◽

Gastric Neoplasia ◽

Endoscopic Classification ◽

Control Study

ObjectivesTo assess the value of endoscopic grading of gastric intestinal metaplasia (EGGIM), operative link on gastritis assessment (OLGA) and operative link on gastric intestinal metaplasia (OLGIM) on risk stratification for early gastric neoplasia (EGN) and to investigate other factors possibly associated with its development.DesignSingle centre, case–control study including 187 patients with EGN treated endoscopically and 187 age-matched and sex-matched control subjects. Individuals were classified according to EGGIM, OLGA and OLGIM systems. EGN risk according to gastritis stages and other clinical parameters was further evaluated.ResultsMore patients with EGN had EGGIM of ≥5 than control subjects (68.6% vs 13.3%, p<0.001). OLGA and OLGIM stages III/IV were more prevalent in patients with EGN than in control subjects (68% vs 11%, p<0.001, and 61% vs 3%, p<0.001, respectively). The three systems were the only parameters significantly related to the risk of EGN in multivariate analysis: for EGGIM 1–4 (adjusted OR (AOR) 12.9, 95% CI 1.4 to 118.6) and EGGIM 5–10 (AOR 21.2, 95% CI 5.0 to 90.2); for OLGA I/II (AOR 5.0, 95% CI 0.56 to 44.5) and OLGA III/IV (AOR 11.1, 95% CI 3.7 to 33.1); for OLGIM I/II (AOR 11.5, 95% CI 4.1 to 32.3) and OLGIM III/IV (AOR 16.0, 95% CI 7.6 to 33.4).ConclusionThis study confirms the role of histological assessment as an independent risk factor for gastric cancer (GC), but it is the first study to show that an endoscopic classification of gastric intestinal metaplasia is highly associated with that outcome. After further prospective validation, this classification may be appropriate for GC risk stratification and may simplify every day practice by reducing the need for biopsies.

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Differentiation reprogramming in gastric intestinal metaplasia and dysplasia: role of SOX2 and CDX2

Histopathology ◽

10.1111/his.12544 ◽

2014 ◽

Vol 66 (3) ◽

pp. 343-350 ◽

Cited By ~ 18

Author(s):

Vânia Camilo ◽

Mónica Garrido ◽

Pedro Valente ◽

Sara Ricardo ◽

Ana Luísa Amaral ◽

...

Keyword(s):

Intestinal Metaplasia ◽

Gastric Intestinal Metaplasia

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MYB transcription factor CiMYB42 regulates limonoids biosynthesis in citrus

10.21203/rs.2.21480/v1 ◽

2020 ◽

Author(s):

pan zhang ◽

Xiaofeng Liu ◽

Xin Xu ◽

Fusheng Wang ◽

Junhong Long ◽

...

Keyword(s):

Transcription Factor ◽

Biosynthetic Pathway ◽

Developmental Stages ◽

Regulatory Mechanisms ◽

Myb Transcription Factor ◽

Transcription Activator ◽

Multiple Alignment Analysis ◽

Citrus Varieties ◽

Alignment Analysis

Abstract Backgrounds Limonoids, a major bioactive components, are produced by triterpenoids metabolic pathway. So far, the detailed biochemical reactions regarding to limonoid biosynthesis and their molecular regulation remain elusive. The identification of transcription factors that regulate limonoids biosynthetic pathways is not only necessary for understanding the regulatory mechanisms but also as a tool for manipulating biosynthetic genes for biotechnological applications.Results In this study, CiMYB42 transcription factor was isolated and identified. Multiple alignment analysis and phylogenetic analysis demonstrated that CiMYB42 is a typical R2R3MYB transcription factor and its amino acid is similar to that of AtMYB42 . The limonoids content was higher in the citrus sinensis and citrus grandis than other species. The diverse accumulation patterns also showed in different leaf developmental stages. Expression of CiMYB42 was significantly related to limonoids content and the expression of CiOSC in some of citrus varieties. CiMYB42 transgenic sweet orange resulted significantly change on limonoids contents. Noticeably, CiMYB42 -RNAi induced dwarf phenotype and mainly decreased nomilin accumulation. Overexpressing CiMYB42 mainly increased limonin content. Yeast one hybrid assay results indicated that CiMYB42 exclusively bind to the promoter of CiOSC. In brief, CiMYB42 involved in the limonoids biosynthesis through binding the promoter of CiOSC in citrus.Conclusions These results indicated that CiMYB42 is an important transcription activator involved in limonoids biosynthesis by regulating the expression of CiOSC . This is the first report elucidating the role of transcription factor in citrus limonoids biosynthesis. Our contributions will provide a reference to understanding regulatory mechanisms of R2R3MYB TFs in the triterpenoids biosynthetic pathway.

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