title: Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci.
abstract: To functionally link coronary artery disease (CAD) causal genes identified by genome wide association studies (GWAS), and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with the CAD associated transcription factor TCF21 in human coronary artery smooth muscle cells (HCASMC). Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including "growth factor binding," "matrix interaction," and "smooth muscle contraction." We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America; Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Olga
authors.initials: O
authors.lastname: Sazonova
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America; Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Nürnberg
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America; Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Clint
authors.initials: C
authors.lastname: Miller
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America; Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Milos
authors.initials: M
authors.lastname: Pjanic
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Castano
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America; Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Juyong B
authors.initials: JB
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America; Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Elias L
authors.initials: EL
authors.lastname: Salfati
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Anshul B
authors.initials: AB
authors.lastname: Kundaje
authors.affiliation: Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America; Department of Computer Science, Stanford University School of Medicine, Stanford, California, United States of America; Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America; Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Gill
authors.initials: G
authors.lastname: Bejerano
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America; Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Themistocles
authors.initials: T
authors.lastname: Assimes
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America; Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
mesh_terms: D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics*; D001665:Binding Sites; D003324:Coronary Artery Disease / Q000235:genetics* / Q000473:pathology; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018808:Transcription Factor AP-1; C491825:TCF21 protein, human