Krüppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3)

• Published in: The Journal of biological chemistry 2016-07, Vol.291 (31), p.16048-16058
• Main Authors: Knights, Alexander J., Yik, Jinfen J., Mat Jusoh, Hanapi, Norton, Laura J., Funnell, Alister P.W., Pearson, Richard C.M., Bell-Anderson, Kim S., Crossley, Merlin, Quinlan, Kate G.R.
• Format: Article
• Language: English
• Subjects: adipose tissue; Animals; galectin; Galectin 3 - biosynthesis; Galectin 3 - genetics; galectin-3 (Lgals3); gene expression; Gene Regulation; Gene Silencing; inflammation; Inflammation Mediators - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Krüppel-like factor (KLF); Krüppel-like factor 3 (KLF3); metabolism; Mice; Mice, Knockout; Repressor Proteins - genetics; Repressor Proteins - metabolism; Response Elements; transcription regulation; Transcription, Genetic
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.715748

The Lgals3 gene encodes a multifunctional β-galactoside-binding protein, galectin-3. Galectin-3 has been implicated in a broad range of biological processes from chemotaxis and inflammation to fibrosis and apoptosis. The role of galectin-3 as a modulator of inflammation has been studied intensively, and recent evidence suggests that it may serve as a protective factor in obesity and other metabolic disorders. Despite considerable interest in galectin-3, little is known about its physiological regulation at the transcriptional level. Here, using knockout mice, chromatin immunoprecipitations, and cellular and molecular analyses, we show that the zinc finger transcription factor Krüppel-like factor 3 (KLF3) directly represses galectin-3 transcription. We find that galectin-3 is broadly up-regulated in KLF3-deficient mouse tissues, that KLF3 occupies regulatory regions of the Lgals3 gene, and that KLF3 directly binds its cognate elements (CACCC boxes) in the galectin-3 promoter and represses its activation in cellular assays. We also provide mechanistic insights into the regulation of Lgals3, demonstrating that C-terminal binding protein (CtBP) is required to drive optimal KLF3-mediated silencing. These findings help to enhance our understanding of how expression of the inflammatory modulator galectin-3 is controlled, opening up avenues for potential therapeutic interventions in the future.