Expression of REG family genes in human inflammatory bowel diseases and its regulation

Biochem Biophys Rep. 2017 Oct 23:12:198-205. doi: 10.1016/j.bbrep.2017.10.003. eCollection 2017 Dec.

Abstract

The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members have been reported to be expressed in Crohn's disease (CD) and ulcerative colitis (UC) and to be involved as proliferative mucosal factors in IBD. However, expression of all REG family genes in IBD is still unclear. Here, we analyzed expression of all REG family genes (REG Iα, REG Iβ, REG III, HIP/PAP, and REG IV) in biopsy specimens of UC and CD by real-time RT-PCR. REG Iα, REG Iβ, and REG IV genes were overexpressed in CD samples. REG IV gene was also overexpressed in UC samples. We further analyzed the expression mechanisms of REG Iα, REG Iβ, and REG IV genes in human colon cells. The expression of REG Iα was significantly induced by IL-6 or IL-22, and REG Iβ was induced by IL-22. Deletion analyses revealed that three regions (- 220 to - 211, - 179 to - 156, and - 146 to - 130) in REG Iα and the region (- 274 to- 260) in REG Iβ promoter were responsible for the activation by IL-22/IL-6. The promoters contain consensus transcription factor binding sequences for MZF1, RTEF1/TEAD4, and STAT3 in REG Iα, and HLTF/FOXN2F in REG Iβ, respectively. The introduction of siRNAs for MZF1, RTEF1/TEAD4, STAT3, and HLTF/FOXN2F abolished the transcription of REG Iα and REG Iβ. The gene activation mechanisms of REG Iα/REG Iβ may play a role in colon mucosal regeneration in IBD.

Keywords: CD, Crohn's disease; CDX2, caudal-type homeobox transcription factor 2; Celiac disease; Crohn's disease; FOXN2, forkhead box protein N2; GATA6, GATA DNA-binding protein 6; HLTF, helicase-like transcription factor; IBD, inflammatory bowel disease; IL, interleukin; MZF1, myeloid zinc finger 1; REG family genes; REG, regenerating gene; RTEF1, related transcriptional enhancer factor-1; SOCS3, suppressors of the cytokine signaling 3; STAT3, signal transducer and activator of transcription 3; TEAD4, TEA Domain transcription Factor 4; Transcription; UC, ulcerative colitis; Ulcerative colitis; siRNA, small interfering RNA.