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DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
BACKGROUND: Epigenetic modifications in mammalian DNA are commonly manifested by DNA methylation. In the stomach, altered DNA methylation patterns have been observed following chronic Helicobacter pylori infections and in gastric cancer. In the context of epigenetic regulation, the regional nature o...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9801550/ https://www.ncbi.nlm.nih.gov/pubmed/36585699 http://dx.doi.org/10.1186/s13148-022-01406-4 |
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author | Fritsche, Kristin Boccellato, Francesco Schlaermann, Philipp Koeppel, Max Denecke, Christian Link, Alexander Malfertheiner, Peter Gut, Ivo Meyer, Thomas F. Berger, Hilmar |
author_facet | Fritsche, Kristin Boccellato, Francesco Schlaermann, Philipp Koeppel, Max Denecke, Christian Link, Alexander Malfertheiner, Peter Gut, Ivo Meyer, Thomas F. Berger, Hilmar |
author_sort | Fritsche, Kristin |
collection | PubMed |
description | BACKGROUND: Epigenetic modifications in mammalian DNA are commonly manifested by DNA methylation. In the stomach, altered DNA methylation patterns have been observed following chronic Helicobacter pylori infections and in gastric cancer. In the context of epigenetic regulation, the regional nature of the stomach has been rarely considered in detail. RESULTS: Here, we establish gastric mucosa derived primary cell cultures as a reliable source of native human epithelium. We describe the DNA methylation landscape across the phenotypically different regions of the healthy human stomach, i.e., antrum, corpus, fundus together with the corresponding transcriptomes. We show that stable regional DNA methylation differences translate to a limited extent into regulation of the transcriptomic phenotype, indicating a largely permissive epigenetic regulation. We identify a small number of transcription factors with novel region-specific activity and likely epigenetic impact in the stomach, including GATA4, IRX5, IRX2, PDX1 and CDX2. Detailed analysis of the Wnt pathway reveals differential regulation along the craniocaudal axis, which involves non-canonical Wnt signaling in determining cell fate in the proximal stomach. By extending our analysis to pre-neoplastic lesions and gastric cancers, we conclude that epigenetic dysregulation characterizes intestinal metaplasia as a founding basis for functional changes in gastric cancer. We present insights into the dynamics of DNA methylation across anatomical regions of the healthy stomach and patterns of its change in disease. Finally, our study provides a well-defined resource of regional stomach transcription and epigenetics. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-022-01406-4. |
format | Online Article Text |
id | pubmed-9801550 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-98015502022-12-31 DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity Fritsche, Kristin Boccellato, Francesco Schlaermann, Philipp Koeppel, Max Denecke, Christian Link, Alexander Malfertheiner, Peter Gut, Ivo Meyer, Thomas F. Berger, Hilmar Clin Epigenetics Research BACKGROUND: Epigenetic modifications in mammalian DNA are commonly manifested by DNA methylation. In the stomach, altered DNA methylation patterns have been observed following chronic Helicobacter pylori infections and in gastric cancer. In the context of epigenetic regulation, the regional nature of the stomach has been rarely considered in detail. RESULTS: Here, we establish gastric mucosa derived primary cell cultures as a reliable source of native human epithelium. We describe the DNA methylation landscape across the phenotypically different regions of the healthy human stomach, i.e., antrum, corpus, fundus together with the corresponding transcriptomes. We show that stable regional DNA methylation differences translate to a limited extent into regulation of the transcriptomic phenotype, indicating a largely permissive epigenetic regulation. We identify a small number of transcription factors with novel region-specific activity and likely epigenetic impact in the stomach, including GATA4, IRX5, IRX2, PDX1 and CDX2. Detailed analysis of the Wnt pathway reveals differential regulation along the craniocaudal axis, which involves non-canonical Wnt signaling in determining cell fate in the proximal stomach. By extending our analysis to pre-neoplastic lesions and gastric cancers, we conclude that epigenetic dysregulation characterizes intestinal metaplasia as a founding basis for functional changes in gastric cancer. We present insights into the dynamics of DNA methylation across anatomical regions of the healthy stomach and patterns of its change in disease. Finally, our study provides a well-defined resource of regional stomach transcription and epigenetics. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-022-01406-4. BioMed Central 2022-12-30 /pmc/articles/PMC9801550/ /pubmed/36585699 http://dx.doi.org/10.1186/s13148-022-01406-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Fritsche, Kristin Boccellato, Francesco Schlaermann, Philipp Koeppel, Max Denecke, Christian Link, Alexander Malfertheiner, Peter Gut, Ivo Meyer, Thomas F. Berger, Hilmar DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity |
title | DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity |
title_full | DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity |
title_fullStr | DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity |
title_full_unstemmed | DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity |
title_short | DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity |
title_sort | dna methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9801550/ https://www.ncbi.nlm.nih.gov/pubmed/36585699 http://dx.doi.org/10.1186/s13148-022-01406-4 |
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