Inference of transcriptional regulation in cancers.

Proc Natl Acad Sci U S A
Authors
Keywords
Abstract

Despite the rapid accumulation of tumor-profiling data and transcription factor (TF) ChIP-seq profiles, efforts integrating TF binding with the tumor-profiling data to understand how TFs regulate tumor gene expression are still limited. To systematically search for cancer-associated TFs, we comprehensively integrated 686 ENCODE ChIP-seq profiles representing 150 TFs with 7484 TCGA tumor data in 18 cancer types. For efficient and accurate inference on gene regulatory rules across a large number and variety of datasets, we developed an algorithm, RABIT (regression analysis with background integration). In each tumor sample, RABIT tests whether the TF target genes from ChIP-seq show strong differential regulation after controlling for background effect from copy number alteration and DNA methylation. When multiple ChIP-seq profiles are available for a TF, RABIT prioritizes the most relevant ChIP-seq profile in each tumor. In each cancer type, RABIT further tests whether the TF expression and somatic mutation variations are correlated with differential expression patterns of its target genes across tumors. Our predicted TF impact on tumor gene expression is highly consistent with the knowledge from cancer-related gene databases and reveals many previously unidentified aspects of transcriptional regulation in tumor progression. We also applied RABIT on RNA-binding protein motifs and found that some alternative splicing factors could affect tumor-specific gene expression by binding to target gene 3'UTR regions. Thus, RABIT (rabit.dfci.harvard.edu) is a general platform for predicting the oncogenic role of gene expression regulators.

Year of Publication
2015
Journal
Proc Natl Acad Sci U S A
Volume
112
Issue
25
Pages
7731-6
Date Published
2015 Jun 23
ISSN
1091-6490
URL
DOI
10.1073/pnas.1424272112
PubMed ID
26056275
PubMed Central ID
PMC4485084
Links
Grant list
U01 CA180980 / CA / NCI NIH HHS / United States
R01 GM113242 / GM / NIGMS NIH HHS / United States
NHGRI U41 HG7000 / PHS HHS / United States
NCI U01 CA180980 / CA / NCI NIH HHS / United States
U41 HG007000 / HG / NHGRI NIH HHS / United States
R01GM113242-01 / GM / NIGMS NIH HHS / United States