BPB Reports

Paper Details

BPB Reports
Vol. 3 No. 6 p.190-195 2020
Regular Article
Transcription of CLDND1 is Regulated Mainly by the Competitive Action of MZF1 and SP1 that Binds to the Enhancer of the Promoter Region
  • Akihiro Michihara (Laboratory of Genomic Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University / mitihara@fukuyama-u.ac.jp)
Akiho Shima , Hiroshi Matsuoka , Takahiro Hamashima , Alice Yamaoka , Yutaro Koga , Akihiro Michihara
Laboratory of Genomic Function and Pathophysiology, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University
Received: October 26, 2020;   Accepted: November 17, 2020;   Released: December 02, 2020
Keywords: claudin, myeloid zinc finger 1, specificity protein 1, tight junctions, stroke, transcriptional regulation

Increased permeability of vascular endothelial cells in the brain is an underlying cause of stroke, which is associated with high mortality rates worldwide. Vascular permeability is regulated by tight junctions (TJs) formed by claudin family and occludin proteins. In particular, increased vascular permeability is associated with decreased claudin domain-containing 1 (CLDND1) expression, which belongs to the TJs family. We previously reported that myeloid zinc finger 1 (MZF1) acts as an activator of CLDND1 expression by binding to its first intron. Several transcription factors regulate transcription by acting on the promoter regions of target genes. However, transcription factors acting on the promoter of CLDND1 are not completely elucidated. Thus, we focused on the promoter region of human CLDND1 to identify factors that could regulate its transcription. Reporter analysis of CLDND1 promoter region revealed an enhancer in the -742/-734 region with MZF1 and specificity protein 1 (SP1) binding sites. Chromatin immunoprecipitation assays confirmed that both MZF1 and SP1 could bind to CLDND1 enhancer region. MZF1 overexpression significantly increased CLDND1 expression, whereas overexpression of SP1 had no effect. Moreover, the identified enhancer region exhibited stronger transcriptional and binding capacity than the first intron. Thus, CLDND1 expression is more strongly regulated by competitive action of MZF1 and SP1 binding to the promoter-enhancer region than the first intron silencer region. These results provide novel insights for the development of potential therapies and preventive strategies for stroke in the future.