title: Suppression of hath1 gene expression directly regulated by hes1 via notch signaling is associated with goblet cell depletion in ulcerative colitis.
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.
authors: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Xiu
authors: X
authors: Zheng
authors: Kiichiro
authors: K
authors: Tsuchiya
authors: Ryuichi
authors: R
authors: Okamoto
authors: Michiko
authors: M
authors: Iwasaki
authors: Yoshihito
authors: Y
authors: Kano
authors: Naoya
authors: N
authors: Sakamoto
authors: Tetsuya
authors: T
authors: Nakamura
authors: Mamoru
authors: M
authors: Watanabe
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D015153:Blotting, Western; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000166:cytology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000071616:CDX2 Transcription Factor; D018398:Homeodomain Proteins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008156:Luciferases; D055262:Mucin-2; D012333:RNA, Messenger; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C500942:ATOH1 protein, human; C491270:CDX2 protein, human; C524625:MUC2 protein, human; C078493:HES1 protein, human