title: Krüppel-like Factor 3 (KLF3/BKLF) Is Required for Widespread Repression of the Inflammatory Modulator Galectin-3 (Lgals3).
abstract: 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.
authors.affiliation: From the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052 and.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Knights
authors.affiliation: From the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052 and.
authors.forename: Jinfen J
authors.initials: JJ
authors.lastname: Yik
authors.affiliation: the School of Molecular Bioscience and.
authors.forename: Hanapi
authors.initials: H
authors.lastname: Mat Jusoh
authors.affiliation: From the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052 and.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Norton
authors.affiliation: From the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052 and.
authors.forename: Alister P W
authors.initials: AP
authors.lastname: Funnell
authors.affiliation: From the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052 and.
authors.forename: Richard C M
authors.initials: RC
authors.lastname: Pearson
authors.affiliation: Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Kim S
authors.initials: KS
authors.lastname: Bell-Anderson
authors.affiliation: From the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052 and.
authors.forename: Merlin
authors.initials: M
authors.lastname: Crossley
authors.affiliation: From the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052 and kate.quinlan@unsw.edu.au.
authors.forename: Kate G R
authors.initials: KG
authors.lastname: Quinlan
mesh_terms: D000818:Animals; D037502:Galectin 3 / Q000096:biosynthesis* / Q000235:genetics; D020868:Gene Silencing; D018836:Inflammation Mediators / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D014158:Transcription, Genetic
chemical_list: D037502:Galectin 3; D018836:Inflammation Mediators; C529780:Klf3 protein, mouse; D051741:Kruppel-Like Transcription Factors; C485095:Lgals3 protein, mouse; D012097:Repressor Proteins
keywords: Krüppel-like factor (KLF); Krüppel-like factor 3 (KLF3); adipose tissue; galectin; galectin-3 (Lgals3); gene expression; gene regulation; inflammation; metabolism; transcription regulation