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Abnormal Genetic and Epigenetic Changes in Signal Transducer and Activator of Transcription 4 in the Pathogenesis of Inflammatory Bowel Diseases

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Abstract

Background and Aims

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.

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Acknowledgments

This work was supported by a grant from the 2009 Good Health R&D Project, Ministry of Health and Welfare, Republic of Korea (grant number A084943), and from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (grant number 2009-0069149), and a faculty research grant from Yeonsei University College of Medicine for 2010 (grant number 6-2010-0021). We would like to thank the blood donors for their contribution to this study.

Conflict of interest

The authors have no conflicts of interest to disclose.

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Author notes

  1. Seung Won Kim

    Present address: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul, Korea

  2. Eun Soo Kim

    Present address: Division of Gastroenterology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea

Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea

    Seung Won Kim, Eun Soo Kim, Chang Mo Moon, Tae Il Kim, Won Ho Kim & Jae Hee Cheon

  2. Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, Korea

    Seung Won Kim, Won Ho Kim & Jae Hee Cheon

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  1. Seung Won Kim
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Correspondence to Jae Hee Cheon.

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Kim, S.W., Kim, E.S., Moon, C.M. et al. Abnormal Genetic and Epigenetic Changes in Signal Transducer and Activator of Transcription 4 in the Pathogenesis of Inflammatory Bowel Diseases. Dig Dis Sci 57, 2600–2607 (2012). https://doi.org/10.1007/s10620-012-2199-z

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