Suppression of hath1 gene expression directly regulated by hes1 via notch signaling is associated with goblet cell depletion in ulcerative colitis

Authors

  • Xiu Zheng MD,

    1. Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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    • The first two authors contributed equally to this work.

  • Kiichiro Tsuchiya MD, PhD,

    1. Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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    • The first two authors contributed equally to this work.

  • Ryuichi Okamoto MD, PhD,

    1. Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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  • Michiko Iwasaki MD, PhD,

    1. Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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  • Yoshihito Kano MD,

    1. Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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  • Naoya Sakamoto MD, PhD,

    1. Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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  • Tetsuya Nakamura MD, PhD,

    1. Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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  • Mamoru Watanabe MD, PhD

    Corresponding author
    1. Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
    • Professor and Chairman, Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
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  • Supported in part by grants-in-aid for Scientific Research 19209027, 21590803, 21790651, and 21790653, from the Japanese Ministry of Education, Culture, Sports, Science and Technology; JFE (Japanese Foundation for Research and Promotion of Endoscopy); Japan Foundation for Applied Enzymology; Intractable Diseases, the Health and Labor Sciences Research Grants from the Japanese Ministry of Health, Labor and Welfare.

Abstract

Background:

The transcription factor Atoh1/Hath1 plays crucial roles in the differentiation program of human intestinal epithelium cells (IECs). Although previous studies have indicated that the Notch signal suppresses the differentiation program of IEC, the mechanism by which it does so remains unknown. This study shows that the undifferentiated state is maintained by the suppression of the Hath1 gene in human intestine.

Methods:

To assess the effect of Notch signaling, doxycycline-induced expression of Notch intracellular domain (NICD) and Hes1 cells were generated in LS174T. Hath1 gene expression was analyzed by quantitative reverse-transcription polymerase chain reaction (RT-PCR). Hath1 promoter region targeted by HES1 was determined by both reporter analysis and ChIP assay. Expression of Hath1 protein in ulcerative colitis (UC) was examined by immunohistochemistry.

Results:

Hath1 mRNA expression was increased by Notch signal inhibition. However, Hath1 expression was suppressed by ectopic HES1 expression alone even under Notch signal inhibition. Suppression of the Hath1 gene by Hes1, which binds to the 5′ promoter region of Hath1, resulted in suppression of the phenotypic gene expression for goblet cells. In UC, the cooperation of aberrant expression of HES1 and the disappearance of caudal type homeobox 2 (CDX2) caused Hath1 suppression, resulting in goblet cell depletion.

Conclusions:

The present study suggests that Hes1 is essential for Hath1 gene suppression via Notch signaling. Moreover, the suppression of Hath1 is associated with goblet cell depletion in UC. Understanding the regulation of goblet cell depletion may lead to the development of new therapy for UC. (Inflamm Bowel Dis 2011;)

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