title: Mucosal transcriptomics implicates under expression of BRINP3 in the pathogenesis of ulcerative colitis.
abstract: BACKGROUND
  Mucosal abnormalities are potentially important in the primary pathogenesis of ulcerative colitis (UC). We investigated the mucosal transcriptomic expression profiles of biopsies from patients with UC and healthy controls, taken from macroscopically noninflamed tissue from the terminal ileum and 3 colonic locations with the objective of identifying abnormal molecules that might be involved in disease development.
  
  
  METHODS
  Whole-genome transcriptional analysis was performed on intestinal biopsies taken from 24 patients with UC, 26 healthy controls, and 14 patients with Crohn's disease. Differential gene expression analysis was performed at each tissue location separately, and results were then meta-analyzed. Significantly, differentially expressed genes were validated using quantitative polymerase chain reaction. The location of gene expression within the colon was determined using immunohistochemistry, subcellular fractionation, electron and confocal microscopy. DNA methylation was quantified by pyrosequencing.
  
  
  RESULTS
  Only 4 probes were abnormally expressed throughout the colon in patients with UC with Bone morphogenetic protein/Retinoic acid Inducible Neural-specific 3 (BRINP3) being the most significantly underexpressed. Attenuated expression of BRINP3 in UC was independent of current inflammation, unrelated to phenotype or treatment, and remained low at rebiopsy an average of 22 months later. BRINP3 is localized to the brush border of the colonic epithelium and expression is influenced by DNA methylation within its promoter.
  
  
  CONCLUSIONS
  Genome-wide expression analysis of noninflamed mucosal biopsies from patients with UC identified BRINP3 as significantly underexpressed throughout the colon in a large subset of patients with UC. Low levels of this gene could predispose or contribute to the maintenance of the characteristic mucosal inflammation seen in this condition.
authors.affiliation: *Centre for Molecular Medicine, Division of Medicine, University College London, London, United Kingdom; †Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, United Kingdom; ‡Medical Genomics, UCL Cancer Institute, University College London, London, United Kingdom; §Division of Bioscience, University College London, London, United Kingdom; ‖Research Pathology and Advanced Diagnostics, UCL Cancer Institute, University College London, London, United Kingdom; and ¶Microbial Diseases, Eastman Dental Institute, University College London, London, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Adam P
authors.initials: AP
authors.lastname: Levine
authors.forename: Jenny
authors.initials: J
authors.lastname: Dunne
authors.forename: Paul
authors.initials: P
authors.lastname: Guilhamon
authors.forename: Mark
authors.initials: M
authors.lastname: Turmaine
authors.forename: Gavin W
authors.initials: GW
authors.lastname: Sewell
authors.forename: Nuala R
authors.initials: NR
authors.lastname: OʼShea
authors.forename: Roser
authors.initials: R
authors.lastname: Vega
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Paterson
authors.forename: Dahmane
authors.initials: D
authors.lastname: Oukrif
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Bloom
authors.forename: Marco
authors.initials: M
authors.lastname: Novelli
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Justo
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Smith
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Segal
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: C528897:BRINP3 protein, human; D015415:Biomarkers; D004268:DNA-Binding Proteins; D012333:RNA, Messenger