title: Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma.
abstract: Despite an emerging understanding of the genetic alterations giving rise to various tumors, the mechanisms whereby most oncogenes are overexpressed remain unclear. Here we have utilized an integrated approach of genomewide regulatory element mapping via DNase-seq followed by conventional reporter assays and transcription factor binding site discovery to characterize the transcriptional regulation of the medulloblastoma oncogene Orthodenticle Homeobox 2 (OTX2). Through these studies we have revealed that OTX2 is differentially regulated in medulloblastoma at the level of chromatin accessibility, which is in part mediated by DNA methylation. In cell lines exhibiting chromatin accessibility of OTX2 regulatory regions, we found that autoregulation maintains OTX2 expression. Comparison of medulloblastoma regulatory elements with those of the developing brain reveals that these tumors engage a developmental regulatory program to drive OTX2 transcription. Finally, we have identified a transcriptional regulatory element mediating retinoid-induced OTX2 repression in these tumors. This work characterizes for the first time the mechanisms of OTX2 overexpression in medulloblastoma. Furthermore, this study establishes proof of principle for applying ENCODE datasets towards the characterization of upstream trans-acting factors mediating expression of individual genes.
authors.affiliation: Department of Pathology, The Pediatric Brain Tumor Foundation Institute, and The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wortham
authors.affiliation: Department of Pathology, The Pediatric Brain Tumor Foundation Institute, and The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Changcun
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Pathology, The Pediatric Brain Tumor Foundation Institute, and The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Monica
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Duke Center for Genomic and Computational Biology, Duke University, Durham, North Carolina, United States of America.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Bum-Kyu
authors.initials: BK
authors.lastname: Lee
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Vishwanath R
authors.initials: VR
authors.lastname: Iyer
authors.affiliation: Department of Genetics, Department of Biology, Carolina Center for Genome Sciences, and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Terrence S
authors.initials: TS
authors.lastname: Furey
authors.affiliation: Duke Center for Genomic and Computational Biology, Duke University, Durham, North Carolina, United States of America; Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Crawford
authors.affiliation: Department of Pathology, The Pediatric Brain Tumor Foundation Institute, and The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Pathology, The Pediatric Brain Tumor Foundation Institute, and The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Yiping
authors.initials: Y
authors.lastname: He
mesh_terms: D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002843:Chromatin / Q000737:chemistry / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D022004:Chromosome Structures / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051857:Otx Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D012176:Retinoids / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D002843:Chromatin; C497659:OTX2 protein, human; D051857:Otx Transcription Factors; D012176:Retinoids; D015534:Trans-Activators