Genome-wide analysis of binding sites and direct target genes of the orphan nuclear receptor NR2F1/COUP-TFI.

PloS One
Celina MontemayorFred A Pereira

Abstract

Identification of bona fide direct nuclear receptor gene targets has been challenging but essential for understanding regulation of organismal physiological processes. We describe a methodology to identify transcription factor binding sites and target genes in vivo by intersecting microarray data, computational binding site queries, and evolutionary conservation. We provide detailed experimental validation of each step and, as a proof of principle, utilize the methodology to identify novel direct targets of the orphan nuclear receptor NR2F1 (COUP-TFI). The first step involved validation of microarray gene expression profiles obtained from wild-type and COUP-TFI(-/-) inner ear tissues. Secondly, we developed a bioinformatic tool to search for COUP-TFI DNA binding sites in genomes, using a classification-type Hidden Markov Model trained with 49 published COUP-TF response elements. We next obtained a ranked list of candidate in vivo direct COUP-TFI targets by integrating the microarray and bioinformatics analyses according to the degree of binding site evolutionary conservation and microarray statistical significance. Lastly, as proof-of-concept, 5 specific genes were validated for direct regulation. For example, the fatty acid bi...Continue Reading

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Datasets Mentioned

BETA
GSE16744

Methods Mentioned

BETA
immunoprecipitation
transgenic
chip
dissections
immunoprecipitation assay
acetylation
ChIPs
immunoprecipitations
phylogenetic footprinting
X-ray

Software Mentioned

GCRMA
UCSC browser
ChromAnalyzer
Consite
HMM
EASE
UCSC Table Browser
dChip
Linux Fedora Core
DAVID

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