title: Dysregulated Lysine Acetyltransferase 2B Promotes Inflammatory Bowel Disease Pathogenesis Through Transcriptional Repression of Interleukin-10.
abstract: OBJECTIVE
  Accumulating evidence supports epigenetic modifications in mediating intestinal immunity in inflammatory bowel disease [IBD] pathogenesis. This study aimed to identify key dysregulated epigenetic modulators and the molecular downstream pathways in IBD.
  
  
  METHODS
  Expression of 116 well-defined epigenetic modulators was profiled and validated in 96 intestinal tissues from patients with Crohn's disease [CD], ulcerative colitis [UC], and healthy controls using quantitative reverse transcriptase polymerase chain reaction [QRT-PCR], western blot, and immunohistochemistry. Dysregulation of histone modifications and IBD-related cytokines were examined by chromatin immunoprecipitation, luciferase activity, and gene expression analyses in normal colonic epithelial cell line, NCM460, upon small-molecule inhibition or RNA interference, followed by validation in primary colonic tissues.
  
  
  RESULTS
  Targeted expression profiling uncovered seven differentially expressed epigenetic modulators, of which the down-regulation of lysine acetyltransferase 2B [KAT2B] mRNA and protein was the most significant and was consequently validated in inflamed CD and UC compared with healthy colonic tissues. KAT2B protein localised abundantly in nuclei of normal colonic epithelium but diminished in paired inflamed CD and UC tissues. Pharmacological inhibition of KAT2B by anacardic acid in NCM460 cells reduced the levels of histone H4 lysine 5 acetylation [H4K5ac] and interleukin-10 [IL-10] in a dose-dependent manner. Knockdown of KAT2B reduced the IL-10 promoter occupancy of KAT2B and H4K5ac, resulting in transcriptional silencing. IL-10 level was also diminished in inflamed IBD tissues.
  
  
  CONCLUSIONS
  Our findings demonstrated a novel epigenetic mechanism of IL-10 dysregulation in IBD. Down-regulation of KAT2B may disrupt the innate and adaptive inflammatory responses due to the suppression of this crucial anti-inflammatory cytokine.
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong SAR Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Alfa H C
authors.initials: AH
authors.lastname: Bai
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong SAR Department of Anaesthesia and Intensive Care, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: William K K
authors.initials: WK
authors.lastname: Wu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Liangliang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong SAR Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Sunny H
authors.initials: SH
authors.lastname: Wong
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong SAR Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Minnie Y
authors.initials: MY
authors.lastname: Go
authors.affiliation: Department of Anatomical and Cellular Pathology, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Anthony W H
authors.initials: AW
authors.lastname: Chan
authors.affiliation: Chelsea and Westminster Hospital, Imperial College London, London, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Harbord
authors.affiliation: Division of Gastroenterology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Shenghong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Division of Gastroenterology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Minhu
authors.initials: M
authors.lastname: Chen
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong SAR Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Justin C Y
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Department of Life Science, National Chung Cheng University, Minxiong, Taiwan.
authors.forename: Michael W Y
authors.initials: MW
authors.lastname: Chan
authors.affiliation: Department of Anaesthesia and Intensive Care, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Matthew T V
authors.initials: MT
authors.lastname: Chan
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong SAR Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Francis K L
authors.initials: FK
authors.lastname: Chan
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong SAR Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong SAR Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong SAR School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
authors.affiliation: Institute of Digestive Disease and State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong SAR Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR.
authors.forename: Siew C
authors.initials: SC
authors.lastname: Ng
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D002460:Cell Line; D003106:Colon / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D042421:Histone Code; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D015415:Biomarkers; D016753:Interleukin-10; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C508609:IL10 protein, human; C000620143:KAT2B protein, human
keywords: Epigenetics; IL-10; KAT2B; histone acetylation