title: Cooperative transcription factor associations discovered using regulatory variation.
abstract: Regulation of gene expression at the transcriptional level is achieved by complex interactions of transcription factors operating at their target genes. Dissecting the specific combination of factors that bind each target is a significant challenge. Here, we describe in detail the Allele Binding Cooperativity test, which uses variation in transcription factor binding among individuals to discover combinations of factors and their targets. We developed the ALPHABIT (a large-scale process to hunt for allele binding interacting transcription factors) pipeline, which includes statistical analysis of binding sites followed by experimental validation, and demonstrate that this method predicts transcription factors that associate with NFκB. Our method successfully identifies factors that have been known to work with NFκB (E2A, STAT1, IRF2), but whose global coassociation and sites of cooperative action were not known. In addition, we identify a unique coassociation (EBF1) that had not been reported previously. We present a general approach for discovering combinatorial models of regulation and advance our understanding of the genetic basis of variation in transcription factor binding.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Karczewski
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Tatonetti
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Landt
authors.forename: Xinqiong
authors.initials: X
authors.lastname: Yang
authors.forename: Teri
authors.initials: T
authors.lastname: Slifer
authors.forename: Russ B
authors.initials: RB
authors.lastname: Altman
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
mesh_terms: D000483:Alleles; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012984:Software; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D014157:Transcription Factors