title: Causal network analysis of head and neck keloid tissue identifies potential master regulators.
abstract: To generate novel insights and hypotheses in keloid development from potential master regulators.
  
  
  
  Prospective cohort.
  
  
  
  Six fresh keloid and six normal skin samples from 12 anonymous donors were used in a prospective cohort study. Genome-wide profiling was done previously on the cohort using the Infinium HumanMethylation450 BeadChip (Illumina, San Diego, CA). The 190 statistically significant CpG islands between keloid and normal tissue mapped to 152 genes (P < .05). The top 10 statistically significant genes (VAMP5, ACTR3C, GALNT3, KCNAB2, LRRC61, SCML4, SYNGR1, TNS1, PLEKHG5, PPP1R13-α, false discovery rate <.015) were uploaded into the Ingenuity Pathway Analysis software's Causal Network Analysis (QIAGEN, Redwood City, CA). To reflect expected gene expression direction in the context of methylation changes, the inverse of the methylation ratio from keloid versus normal tissue was used for the analysis. Causal Network Analysis identified disease-specific master regulator molecules based on downstream differentially expressed keloid-specific genes and expected directionality of expression (hypermethylated vs. hypomethylated).
  
  
  
  Causal Network Analysis software identified four hierarchical networks that included four master regulators (pyroxamide, tributyrin, PRKG2, and PENK) and 19 intermediate regulators.
  
  
  
  Causal Network Analysis of differentiated methylated gene data of keloid versus normal skin demonstrated four causal networks with four master regulators. These hierarchical networks suggest potential driver roles for their downstream keloid gene targets in the pathogenesis of the keloid phenotype, likely triggered due to perturbation/injury to normal tissue.
  
  
  
  NA Laryngoscope, 126:E319-E324, 2016.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Henry Ford Hospital, Detroit, Michigan, U.S.A.
authors.forename: Laura
authors.initials: L
authors.lastname: Garcia-Rodriguez
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Henry Ford Hospital, Detroit, Michigan, U.S.A. ljones5@hfhs.org.
authors.forename: Lamont
authors.initials: L
authors.lastname: Jones
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Henry Ford Hospital, Detroit, Michigan, U.S.A.
authors.forename: Kang Mei
authors.initials: KM
authors.lastname: Chen
authors.affiliation: Department of Public Health Sciences Center for Bioinformatics, Henry Ford Health System, Detroit, Michigan, U.S.A.
authors.forename: Indrani
authors.initials: I
authors.lastname: Datta
authors.affiliation: Department of Public Health Sciences Center for Bioinformatics, Henry Ford Health System, Detroit, Michigan, U.S.A.
authors.forename: George
authors.initials: G
authors.lastname: Divine
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Henry Ford Hospital, Detroit, Michigan, U.S.A.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Worsham
mesh_terms: D000631:Aminopyridines / Q000378:metabolism; D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics; D062967:Cyclic GMP-Dependent Protein Kinase Type II / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004745:Enkephalins / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D005809:Genes, Regulator / Q000235:genetics*; D006257:Head / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D007627:Keloid / Q000235:genetics* / Q000473:pathology; D009333:Neck / Q000473:pathology; D011446:Prospective Studies; D011498:Protein Precursors / Q000235:genetics; D012867:Skin / Q000473:pathology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D004745:Enkephalins; D006877:Hydroxamic Acids; D011498:Protein Precursors; D014280:Triglycerides; C029992:proenkephalin; C428024:pyroxamide; D062967:Cyclic GMP-Dependent Protein Kinase Type II; C569729:PRKG2 protein, human; C005830:tributyrin
keywords: DNA methylation; causal network; fibroblast; keloids; master regulators