Dataset Information

Methylation-dependent activation of CDX1 through NF-?B: a link from inflammation to intestinal metaplasia in the human stomach.

ABSTRACT: The caudal homeobox factor 1 (CDX1) is an essential transcription factor for intestinal differentiation. Its aberrant expression in intestinal metaplasia of the upper gastrointestinal tract is a hallmark within the gastritis-metaplasia-carcinoma sequence. CDX1 expression is influenced by certain pathways, such as Wnt, Ras, or NF-?B signaling; however, these pathways alone cannot explain the transient expression of CDX1 in intestinal metaplasia or the molecular inactivation mechanism of its loss in cases of advanced gastric cancer. In this study, we investigated the epigenetic inactivation of CDX1 by promoter methylation, as well as the functional link of CDX1 promoter methylation to the inflammatory NF-?B signaling pathway. We identified methylation-dependent NF-?B binding to the CDX1 promoter and quantified it using competitive electrophoretic mobility shift assays and chromatin immunoprecipitation. A methylated CDX1 promoter was associated with closed chromatin structure, reduced NF-?B binding, and transcriptional silencing. Along the gastritis-metaplasia-carcinoma sequence, we observed a biphasic pattern of tumor necrosis factor-? (TNF-?) protein expression and an inverse biphasic pattern of CDX1 promoter methylation; both are highly consistent with CDX1 protein expression. The stages of hyper-, hypo-, and hyper-methylation patterns of the CDX1 promoter were inversely correlated with the NF-?B signaling activity along this sequence. In conclusion, these functionally interacting events drive CDX1 expression and contribute to intestinal metaplasia, epithelial dedifferentiation, and carcinogenesis in the human stomach.

SUBMITTER: Rau TT

PROVIDER: S-EPMC3409443 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Methylation-dependent activation of CDX1 through NF-κB: a link from inflammation to intestinal metaplasia in the human stomach.

Rau Tilman T TT Rogler Anja A Frischauf Myrjam M Jung Andreas A Konturek Peter C PC Dimmler Arno A Faller Gerhard G Sehnert Bettina B El-Rifai Wael W Hartmann Arndt A Voll Reinhard E RE Schneider-Stock Regine R

The American journal of pathology 20120627 2

The caudal homeobox factor 1 (CDX1) is an essential transcription factor for intestinal differentiation. Its aberrant expression in intestinal metaplasia of the upper gastrointestinal tract is a hallmark within the gastritis-metaplasia-carcinoma sequence. CDX1 expression is influenced by certain pathways, such as Wnt, Ras, or NF-κB signaling; however, these pathways alone cannot explain the transient expression of CDX1 in intestinal metaplasia or the molecular inactivation mechanism of its loss ...[more]

PMID: 22749770

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Project description:Background & Aims: Tissue metaplasia is uncommon in adults because established cis-element programs resist rewiring. In Barrett’s esophagus, the distal esophageal mucosa acquires predominantly intestinal character, with notable gastric features, and is predisposed to develop invasive cancers. We sought to understand the chromatin underpinnings of Barrett’s metaplasia and why it commonly displays simultaneous gastric and intestinal properties. Methods: We profiled cis-regulatory elements with active histone modifications in primary human biopsy materials using chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Mutations in Barrett’s esophagus were examined in relation to tissue-specific enhancer landscapes using a random-forest machine learning algorithm. We also profiled open chromatin at single-cell resolution in primary Barrett’s biopsy specimens using the assay for transposase-accessible chromatin (ATAC-seq). We used one- and two-color immunohistochemistry to examine protein expression of tissue-restricted genes. Results: Barrett’s esophagus bears epigenome fingerprints of human stomach and intestinal columnar, but not esophageal squamous, epithelia. Mutational patterns were best explained as arising on the epigenome background of active gastric cis-elements, supporting the view that adjoining stomach epithelium is a likely tissue source. Individual cells in Barrett’s metaplasia co-express gastric and intestinal genes, reflecting concomitant chromatin access at enhancers ordinarily restricted to one or the other epithelium. Protein expression of stomach-specific mucins, CLDN18, and a novel gastric marker, ANXA10, revealed extensive tissue and sub-clonal heterogeneity of dual stomach-intestinal cell states. Conclusions: These findings reveal mixed and dynamic tissue-restricted chromatin states and phenotypic heterogeneity in Barrett’s esophagus. Pervasive intra-gland variation argues against stem-cell governance of this phenotype.

Dataset Information

Methylation-dependent activation of CDX1 through NF-?B: a link from inflammation to intestinal metaplasia in the human stomach.

Publications

Methylation-dependent activation of CDX1 through NF-κB: a link from inflammation to intestinal metaplasia in the human stomach.

Similar Datasets

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