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PMID: 21917857 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

An integrative genomic approach identifies p73 and p63 as activators of miR-200 microRNA family transcription.

Nucleic acids research ·Vol. 40 ·No. 2 ·2012-01-00 ·Pages 499-510

Knouf EC, Garg K, Arroyo JD, Correa Y, Sarkar D, Parkin RK, Wurz K, O'Briant KC, Godwin AK, Urban ND, Ruzzo WL, Gentleman R, Drescher CW, Swisher EM, Tewari M

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.

MeSH Terms
Binding Sites Carcinoma/genetics,metabolism Cell Line, Tumor DNA-Binding Proteins/metabolism Female Genome, Human Genomics/methods Humans MicroRNAs/biosynthesis,genetics Molecular Sequence Annotation Nuclear Proteins/metabolism Ovarian Neoplasms/genetics,metabolism Promoter Regions, Genetic Transcription Factors/metabolism Transcription Initiation Site Transcriptional Activation Tumor Protein p73 Tumor Suppressor Proteins/metabolism
Chemicals
DNA-Binding Proteins MIRN200 microRNA, human MicroRNAs Nuclear Proteins TP63 protein, human TP73 protein, human Transcription Factors Tumor Protein p73 Tumor Suppressor Proteins
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Knouf Emily C
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Garg Kavita
Arroyo Jason D
Correa Yesenia
Sarkar Deepayan
Parkin Rachael K
Wurz Kaitlyn
O'Briant Kathy C
Godwin Andrew K
Urban Nicole D
Ruzzo Walter L
Gentleman Robert
Drescher Charles W
Swisher Elizabeth M
Tewari Muneesh
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
DOI
10.1093/nar/gkr731
Published
2012-01-00
Epub
2011-00-14
Pages
499-510
Language
English
Region
England
NLM ID
0411011
PMCID
PMC3258134
Subset
IM
Grants
NCI NIH HHS · HHSN261200800001E · United States
NCI NIH HHS · R01 CA140323 · United States
NCI NIH HHS · P30 CA015704 · United States
NIGMS NIH HHS · T32 GM07270 · United States
NCI NIH HHS · CA09657 · United States
NCI NIH HHS · R01 CA106588 · United States
NCI NIH HHS · P50CA083636 · United States
NCI NIH HHS · T32 CA080416 · United States
NCI NIH HHS · P50 CA083636 · United States
NCI NIH HHS · CA80416 · United States
External Links
PubMed source DOI: 10.1093/nar/gkr731 PMC Full Text View journal details
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