title: Abnormal genetic and epigenetic changes in signal transducer and activator of transcription 4 in the pathogenesis of inflammatory bowel diseases.
abstract: OBJECTIVE
  Changes in the expression of signal transducer and activator of transcription 4 (STAT4) contribute to the development of a variety of autoimmune diseases including inflammatory bowel diseases (IBDs). Moreover, epigenetic modifications, including DNA methylation, are considered a basis for differentiation of T helper cells and regulation of cytokines. In this study, we investigated the methylation status of STAT4 gene in IBD patients and the associations between its genetic and epigenetic alterations in IBD patients.
  
  
  METHODS
  Blood and colonic mucosa samples were obtained from Korean patients with IBD and healthy controls. Peripheral blood mononuclear cells (PBMCs) were isolated, and total RNA and genomic DNA were isolated from the PBMCs and colon mucosa tissues. The mRNA level and DNA methylation status of the promoter were determined by real-time RT-PCR and pyrosequencing, respectively. The chosen SNPs (rs11889341, rs7574865, rs8179673, rs6752770, rs925847, rs10168266, rs10181656, and rs11685878) were genotyped using the TaqMan nuclease assay.
  
  
  RESULTS
  Elevated expression of STAT4 was observed in the colonic mucosa and PBMCs of IBD patients. IBD patients showed a lower degree of methylation of the STAT4 promoter than did the healthy controls. Moreover, a significant correlation between risk alleles and methylation status at -172 of the STAT4 promoter was observed, and mRNA levels of STAT4 in IBD patients were correlated inversely with the T-risk allele (rs7574865).
  
  
  CONCLUSIONS
  Our data demonstrated that the DNA methylation status of STAT4 is associated with genetic polymorphisms, providing insights into the interactions between genetic and epigenetic aberrances in STAT4 that contribute to the development of IBD.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea.
authors.forename: Seung Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Eun Soo
authors.initials: ES
authors.lastname: Kim
authors.forename: Chang Mo
authors.initials: CM
authors.lastname: Moon
authors.forename: Tae Il
authors.initials: TI
authors.lastname: Kim
authors.forename: Won Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Jae Hee
authors.initials: JH
authors.lastname: Cheon
mesh_terms: D044466:Asian People; D016022:Case-Control Studies; D003106:Colon; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D007413:Intestinal Mucosa; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D004247:DNA