title: An integrative genomic approach identifies p73 and p63 as activators of miR-200 microRNA family transcription.
abstract: Although microRNAs (miRNAs) are important regulators of gene expression, the transcriptional regulation of miRNAs themselves is not well understood. We employed an integrative computational pipeline to dissect the transcription factors (TFs) responsible for altered miRNA expression in ovarian carcinoma. Using experimental data and computational predictions to define miRNA promoters across the human genome, we identified TFs with binding sites significantly overrepresented among miRNA genes overexpressed in ovarian carcinoma. This pipeline nominated TFs of the p53/p63/p73 family as candidate drivers of miRNA overexpression. Analysis of data from an independent set of 253 ovarian carcinomas in The Cancer Genome Atlas showed that p73 and p63 expression is significantly correlated with expression of miRNAs whose promoters contain p53/p63/p73 family binding sites. In experimental validation of specific miRNAs predicted by the analysis to be regulated by p73 and p63, we found that p53/p63/p73 family binding sites modulate promoter activity of miRNAs of the miR-200 family, which are known regulators of cancer stem cells and epithelial-mesenchymal transitions. Furthermore, in chromatin immunoprecipitation studies both p73 and p63 directly associated with the miR-200b/a/429 promoter. This study delineates an integrative approach that can be applied to discover transcriptional regulatory mechanisms in other biological settings where analogous genomic data are available.
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Knouf
authors.forename: Kavita
authors.initials: K
authors.lastname: Garg
authors.forename: Jason D
authors.initials: JD
authors.lastname: Arroyo
authors.forename: Yesenia
authors.initials: Y
authors.lastname: Correa
authors.forename: Deepayan
authors.initials: D
authors.lastname: Sarkar
authors.forename: Rachael K
authors.initials: RK
authors.lastname: Parkin
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Wurz
authors.forename: Kathy C
authors.initials: KC
authors.lastname: O'Briant
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Urban
authors.forename: Walter L
authors.initials: WL
authors.lastname: Ruzzo
authors.forename: Robert
authors.initials: R
authors.lastname: Gentleman
authors.forename: Charles W
authors.initials: CW
authors.lastname: Drescher
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
authors.forename: Muneesh
authors.initials: M
authors.lastname: Tewari
mesh_terms: D001665:Binding Sites; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D058977:Molecular Sequence Annotation; D009687:Nuclear Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*; D024363:Transcription Initiation Site; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins