title: The effect of non-coding DNA variations on P53 and cMYC competitive inhibition at cis-overlapping motifs.
abstract: Non-coding DNA variations play a critical role in increasing the risk for development of common complex diseases, and account for the majority of SNPs highly associated with cancer. However, it remains a challenge to identify etiologic variants and to predict their pathological effects on target gene expression for clinical purposes. Cis-overlapping motifs (COMs) are elements of enhancer regions that impact gene expression by enabling competitive binding and switching between transcription factors. Mutations within COMs are especially important when the involved transcription factors have opposing effects on gene regulation, like P53 tumor suppressor and cMYC proto-oncogene. In this study, genome-wide analysis of ChIP-seq data from human cancer and mouse embryonic cells identified a significant number of putative regulatory elements with signals for both P53 and cMYC. Each co-occupied element contains, on average, two COMs, and one common SNP every two COMs. Gene ontology of predicted target genes for COMs showed that the majority are involved in DNA damage, apoptosis, cell cycle regulation, and RNA processing. EMSA results showed that both cMYC and P53 bind to cis-overlapping motifs within a ChIP-seq co-occupied region in Chr12. In vitro functional analysis of selected co-occupied elements verified enhancer activity, and also showed that the occurrence of SNPs within three COMs significantly altered enhancer activity. We identified a list of COM-associated functional SNPs that are in close proximity to SNPs associated with common diseases in large population studies. These results suggest a potential molecular mechanism to identify etiologic regulatory mutations associated with common diseases.
authors.affiliation: Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX 77054, USA and.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kin
authors.affiliation: Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX 77054, USA and.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Gonzalez-Garay
authors.affiliation: Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX 77054, USA and walid.d.fakhouri@uth.tmc.edu.
authors.forename: Walid D
authors.initials: WD
authors.lastname: Fakhouri
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D015894:Genome, Human; D006801:Humans; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: C000715470:MAS1 protein, human; C489427:MYC protein, human; C489428:Myc protein, mouse; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA