title: Creating and validating cis-regulatory maps of tissue-specific gene expression regulation.
abstract: Predicting which genomic regions control the transcription of a given gene is a challenge. We present a novel computational approach for creating and validating maps that associate genomic regions (cis-regulatory modules-CRMs) with genes. The method infers regulatory relationships that explain gene expression observed in a test tissue using widely available genomic data for 'other' tissues. To predict the regulatory targets of a CRM, we use cross-tissue correlation between histone modifications present at the CRM and expression at genes within 1 Mbp of it. To validate cis-regulatory maps, we show that they yield more accurate models of gene expression than carefully constructed control maps. These gene expression models predict observed gene expression from transcription factor binding in the CRMs linked to that gene. We show that our maps are able to identify long-range regulatory interactions and improve substantially over maps linking genes and CRMs based on either the control maps or a 'nearest neighbor' heuristic. Our results also show that it is essential to include CRMs predicted in multiple tissues during map-building, that H3K27ac is the most informative histone modification, and that CAGE is the most informative measure of gene expression for creating cis-regulatory maps.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Queensland, Australia.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: O'Connor
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Queensland, Australia t.bailey@uq.edu.au.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Bailey
mesh_terms: D002460:Cell Line; D005786:Gene Expression Regulation; D023281:Genomics / Q000379:methods; D006657:Histones / Q000032:analysis; D006801:Humans; D016014:Linear Models; D008957:Models, Genetic; D009928:Organ Specificity; D014157:Transcription Factors / Q000378:metabolism; D024363:Transcription Initiation Site
chemical_list: D006657:Histones; D014157:Transcription Factors