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SOX15 Governs Transcription in Human Stratified Epithelia and a Subset of Esophageal Adenocarcinomas
BACKGROUND & AIMS: Intestinal metaplasia (Barrett’s esophagus, BE) is the principal risk factor for esophageal adenocarcinoma (EAC). Study of the basis for BE has centered on intestinal factors, but loss of esophageal identity likely also reflects the absence of key squamous-cell factors. As few...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620585/ https://www.ncbi.nlm.nih.gov/pubmed/26516633 http://dx.doi.org/10.1016/j.jcmgh.2015.07.009 |
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author | Sulahian, Rita Chen, Justina Arany, Zoltan Jadhav, Unmesh Peng, Shouyong Rustgi, Anil K. Bass, Adam J. Srivastava, Amitabh Hornick, Jason L. Shivdasani, Ramesh A. |
author_facet | Sulahian, Rita Chen, Justina Arany, Zoltan Jadhav, Unmesh Peng, Shouyong Rustgi, Anil K. Bass, Adam J. Srivastava, Amitabh Hornick, Jason L. Shivdasani, Ramesh A. |
author_sort | Sulahian, Rita |
collection | PubMed |
description | BACKGROUND & AIMS: Intestinal metaplasia (Barrett’s esophagus, BE) is the principal risk factor for esophageal adenocarcinoma (EAC). Study of the basis for BE has centered on intestinal factors, but loss of esophageal identity likely also reflects the absence of key squamous-cell factors. As few determinants of stratified epithelial cell-specific gene expression have been characterized, identifying the necessary transcription factors is important. METHODS: We tested regional expression of mRNAs for all putative DNA-binding proteins in the mouse digestive tract and verified the esophagus-specific factors in human tissues and cell lines. Integration of diverse data defined a human squamous esophagus-specific transcriptome. We used chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) to locate transcription factor binding sites, computational approaches to profile the transcripts in cancer data sets, and immunohistochemistry to reveal protein expression. RESULTS: The transcription factor Sex-determining region Y-box 15 (SOX15) is restricted to esophageal and other murine and human stratified epithelia. SOX15 mRNA levels are attenuated in BE, and its depletion in human esophageal cells reduces esophageal transcripts significantly and specifically. SOX15 binding is highly enriched near esophagus-expressed genes, indicating direct transcriptional control. SOX15 and hundreds of genes coexpressed in squamous cells are reactivated in up to 30% of EAC specimens. Genes normally confined to the esophagus or intestine appear in different cells within the same malignant glands. CONCLUSIONS: These data identify a novel transcriptional regulator of stratified epithelial cells and a subtype of EAC with bi-lineage gene expression. Broad activation of squamous-cell genes may shed light on whether EACs arise in the native stratified epithelium or in ectopic columnar cells. |
format | Online Article Text |
id | pubmed-4620585 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-46205852016-11-01 SOX15 Governs Transcription in Human Stratified Epithelia and a Subset of Esophageal Adenocarcinomas Sulahian, Rita Chen, Justina Arany, Zoltan Jadhav, Unmesh Peng, Shouyong Rustgi, Anil K. Bass, Adam J. Srivastava, Amitabh Hornick, Jason L. Shivdasani, Ramesh A. Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: Intestinal metaplasia (Barrett’s esophagus, BE) is the principal risk factor for esophageal adenocarcinoma (EAC). Study of the basis for BE has centered on intestinal factors, but loss of esophageal identity likely also reflects the absence of key squamous-cell factors. As few determinants of stratified epithelial cell-specific gene expression have been characterized, identifying the necessary transcription factors is important. METHODS: We tested regional expression of mRNAs for all putative DNA-binding proteins in the mouse digestive tract and verified the esophagus-specific factors in human tissues and cell lines. Integration of diverse data defined a human squamous esophagus-specific transcriptome. We used chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) to locate transcription factor binding sites, computational approaches to profile the transcripts in cancer data sets, and immunohistochemistry to reveal protein expression. RESULTS: The transcription factor Sex-determining region Y-box 15 (SOX15) is restricted to esophageal and other murine and human stratified epithelia. SOX15 mRNA levels are attenuated in BE, and its depletion in human esophageal cells reduces esophageal transcripts significantly and specifically. SOX15 binding is highly enriched near esophagus-expressed genes, indicating direct transcriptional control. SOX15 and hundreds of genes coexpressed in squamous cells are reactivated in up to 30% of EAC specimens. Genes normally confined to the esophagus or intestine appear in different cells within the same malignant glands. CONCLUSIONS: These data identify a novel transcriptional regulator of stratified epithelial cells and a subtype of EAC with bi-lineage gene expression. Broad activation of squamous-cell genes may shed light on whether EACs arise in the native stratified epithelium or in ectopic columnar cells. Elsevier 2015-08-05 /pmc/articles/PMC4620585/ /pubmed/26516633 http://dx.doi.org/10.1016/j.jcmgh.2015.07.009 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Sulahian, Rita Chen, Justina Arany, Zoltan Jadhav, Unmesh Peng, Shouyong Rustgi, Anil K. Bass, Adam J. Srivastava, Amitabh Hornick, Jason L. Shivdasani, Ramesh A. SOX15 Governs Transcription in Human Stratified Epithelia and a Subset of Esophageal Adenocarcinomas |
title | SOX15 Governs Transcription in Human Stratified Epithelia and a Subset of Esophageal Adenocarcinomas |
title_full | SOX15 Governs Transcription in Human Stratified Epithelia and a Subset of Esophageal Adenocarcinomas |
title_fullStr | SOX15 Governs Transcription in Human Stratified Epithelia and a Subset of Esophageal Adenocarcinomas |
title_full_unstemmed | SOX15 Governs Transcription in Human Stratified Epithelia and a Subset of Esophageal Adenocarcinomas |
title_short | SOX15 Governs Transcription in Human Stratified Epithelia and a Subset of Esophageal Adenocarcinomas |
title_sort | sox15 governs transcription in human stratified epithelia and a subset of esophageal adenocarcinomas |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620585/ https://www.ncbi.nlm.nih.gov/pubmed/26516633 http://dx.doi.org/10.1016/j.jcmgh.2015.07.009 |
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