title: ChIP-BIT: Bayesian inference of target genes using a novel joint probabilistic model of ChIP-seq profiles.
abstract: Chromatin immunoprecipitation with massively parallel DNA sequencing (ChIP-seq) has greatly improved the reliability with which transcription factor binding sites (TFBSs) can be identified from genome-wide profiling studies. Many computational tools are developed to detect binding events or peaks, however the robust detection of weak binding events remains a challenge for current peak calling tools. We have developed a novel Bayesian approach (ChIP-BIT) to reliably detect TFBSs and their target genes by jointly modeling binding signal intensities and binding locations of TFBSs. Specifically, a Gaussian mixture model is used to capture both binding and background signals in sample data. As a unique feature of ChIP-BIT, background signals are modeled by a local Gaussian distribution that is accurately estimated from the input data. Extensive simulation studies showed a significantly improved performance of ChIP-BIT in target gene prediction, particularly for detecting weak binding signals at gene promoter regions. We applied ChIP-BIT to find target genes from NOTCH3 and PBX1 ChIP-seq data acquired from MCF-7 breast cancer cells. TF knockdown experiments have initially validated about 30% of co-regulated target genes identified by ChIP-BIT as being differentially expressed in MCF-7 cells. Functional analysis on these genes further revealed the existence of crosstalk between Notch and Wnt signaling pathways.
authors.affiliation: Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, 900 North Glebe Road, Arlington, VA 22203, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB-II, Baltimore, MD 21231, USA.
authors.forename: Jin-Gyoung
authors.initials: JG
authors.lastname: Jung
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC 20057, USA.
authors.forename: Ayesha N
authors.initials: AN
authors.lastname: Shajahan-Haq
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC 20057, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB-II, Baltimore, MD 21231, USA.
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
authors.affiliation: Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, 900 North Glebe Road, Arlington, VA 22203, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery and Cancer, Imperial College London, ICTEM building, Hammersmith Hospital, DuCane Road, London W120NN, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Magnani
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB-II, Baltimore, MD 21231, USA.
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Wang
authors.affiliation: Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, 900 North Glebe Road, Arlington, VA 22203, USA xuan@vt.edu.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xuan
mesh_terms: D001499:Bayes Theorem; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation / Q000379:methods*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D015233:Models, Statistical; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism; D017422:Sequence Analysis, DNA / Q000379:methods*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C499374:NOTCH3 protein, human; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D014157:Transcription Factors; C083400:PBX1 protein, human