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PMID: 22929615 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Inferring transcriptional and microRNA-mediated regulatory programs in glioblastoma.

Molecular systems biology ·Vol. 8 ·2012-00-00 ·Pages 605

Setty M, Helmy K, Khan AA, Silber J, Arvey A, Neezen F, Agius P, Huse JT, Holland EC, Leslie CS

Abstract

Large-scale cancer genomics projects are profiling hundreds of tumors at multiple molecular layers, including copy number, mRNA and miRNA expression, but the mechanistic relationships between these layers are often excluded from computational models. We developed a supervised learning framework for integrating molecular profiles with regulatory sequence information to reveal regulatory programs in cancer, including miRNA-mediated regulation. We applied our approach to 320 glioblastoma profiles and identified key miRNAs and transcription factors as common or subtype-specific drivers of expression changes. We confirmed that predicted gene expression signatures for proneural subtype regulators were consistent with in vivo expression changes in a PDGF-driven mouse model. We tested two predicted proneural drivers, miR-124 and miR-132, both underexpressed in proneural tumors, by overexpression in neurospheres and observed a partial reversal of corresponding tumor expression changes. Computationally dissecting the role of miRNAs in cancer may ultimately lead to small RNA therapeutics tailored to subtype or individual.

MeSH Terms
Animals Cell Line, Tumor Gene Expression Profiling Gene Expression Regulation, Neoplastic Genome, Human Genomics Glioblastoma/genetics Humans Mice Mice, Transgenic MicroRNAs/genetics,metabolism Models, Biological Neural Stem Cells/metabolism RNA, Messenger/genetics,metabolism Regression Analysis Transcription Factors/genetics
Chemicals
MIRN132 microRNA, mouse MicroRNAs Mirn124 microRNA, mouse RNA, Messenger Transcription Factors
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Setty Manu
Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Helmy Karim
Khan Aly A
Silber Joachim
Arvey Aaron
Neezen Frank
Agius Phaedra
Huse Jason T
Holland Eric C
Leslie Christina S
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Article Info
Journal
Molecular systems biology
Abbr.
Mol Syst Biol
ISSN
1744-4292
DOI
10.1038/msb.2012.37
Published
2012-00-00
Pages
605
Language
English
Region
England
NLM ID
101235389
PMCID
PMC3435504
Subset
IM
Grants
NCI NIH HHS · U24 CA143840 · United States
NCI NIH HHS · U24CA143840 · United States
External Links
PubMed source DOI: 10.1038/msb.2012.37 PMC Full Text View journal details
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