title: SOX15 governs transcription in human stratified epithelia and a subset of esophageal adenocarcinomas.
abstract: OBJECTIVE
  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 absence of key squamous-cell factors. As few determinants of stratified epithelial cell-specific gene expression are characterized, it is important to identify the necessary transcription factors.
  
  
  METHODS
  We tested regional expression of mRNAs for all putative DNA-binding proteins in the mouse digestive tract and verified esophagus-specific factors in human tissues and cell lines. Integration of diverse data defined a human squamous esophagus-specific transcriptome. We used chromatin immunoprecipitation (ChIP-seq) to locate transcription factor binding sites, computational approaches to profile transcripts in cancer datasets, and immunohistochemistry to reveal protein expression.
  
  
  RESULTS
  The transcription factor SOX15 is restricted to esophageal and other murine and human stratified epithelia.SOX15mRNA levels are attenuated in BE and its depletion in human esophageal cells reduced esophageal transcripts significantly and specifically. SOX15 binding is highly enriched near esophagus-expressed genes, indicating direct transcriptional control.SOX15and hundreds of genes co-expressed 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA ; Department of Medicine, Harvard Medical School, 45 Shattuck Street, Boston, MA 02115, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Sulahian
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Justina
authors.initials: J
authors.lastname: Chen
authors.affiliation: Cardiovascular Institute, Perelman School of Medicine, 3620 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Arany
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA ; Department of Medicine, Harvard Medical School, 45 Shattuck Street, Boston, MA 02115, USA.
authors.forename: Unmesh
authors.initials: U
authors.lastname: Jadhav
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Shouyong
authors.initials: S
authors.lastname: Peng
authors.affiliation: Division of Gastroenterology, Departments of Medicine and Genetics, Perelman School of Medicine, 3620 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA ; Department of Medicine, Harvard Medical School, 45 Shattuck Street, Boston, MA 02115, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.affiliation: Departments of Pathology, Brigham & Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Amitabh
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Departments of Pathology, Brigham & Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA ; Department of Medicine, Harvard Medical School, 45 Shattuck Street, Boston, MA 02115, USA.
authors.forename: Ramesh A
authors.initials: RA
authors.lastname: Shivdasani
keywords: Barrett's esophagus; Esophageal gene regulation; SOX15 cistrome; esophageal transcriptome