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Role for Kr??ppel-like transcription factor 11 in mesenchymal cell function and fibrosis. PLoS One 2013;8(9):e75311

Date

09/27/2013

Pubmed ID

24069400

Pubmed Central ID

PMC3775729

DOI

10.1371/journal.pone.0075311

Scopus ID

2-s2.0-84884265835   21 Citations

Abstract

Kr??ppel-like factor 11 (KLF11) and the highly homologous KLF10 proteins are transcription factors originating from duplication of the Drosophila melanogaster ancestor cabut. The function of these proteins in epithelial cells has been previously characterized. In the current study, we report a functional role for KLF11 in mesenchymal cells and in mesenchymal cell dysfunction, namely, fibrosis, and subsequently perform a detailed cellular, molecular, and in vivo characterization of this phenomenon. We find that, in cultured mesenchymal cells, enhanced expression of KLF11 results in activated extracellular matrix pathways, including collagen gene silencing and matrix metalloproteinases activation without changes in tissue inhibitors of metalloproteinases. Combined, reporter and chromatin immunoprecipitation assays demonstrate that KLF11 interacts directly with the collagen 1a2 (COL1A2) promoter in mesenchymal cells to repress its activity. Mechanistically, KLF11 regulates collagen gene expression through the heterochromatin protein 1 gene-silencing pathway as mutants defective for coupling to this epigenetic modifier lose the ability to repress COL1A2. Expression studies reveal decreased levels of KLF11 during liver fibrogenesis after chemically induced injury in vivo. Congruently, KLF11(-/-) mice, which should be deficient in the hypothesized anti-fibrogenic brake imposed by this transcription factor, display an enhanced response to liver injury with increased collagen fibril deposition. Thus, KLFs expands the repertoire of transcription factors involved in the regulation of extracellular matrix proteins in mesenchymal cells and define a novel pathway that modulates the fibrogenic response during liver injury.

Author List

Mathison A, Grzenda A, Lomberk G, Velez G, Buttar N, Tietz P, Hendrickson H, Liebl A, Xiong YY, Gores G, Fernandez-Zapico M, Larusso NF, Faubion W, Shah VH, Urrutia R

Authors

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin
Angela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis Regulatory Proteins
Carbon Tetrachloride
Cell Line
Chemical and Drug Induced Liver Injury
Chromatin Assembly and Disassembly
Chromosomal Proteins, Non-Histone
Collagen Type I
DNA-Binding Proteins
Extracellular Matrix
Fibrosis
Gene Expression Regulation
Gene Silencing
Histone-Lysine N-Methyltransferase
Humans
Mice
Mice, Knockout
Repressor Proteins
Signal Transduction
Transcription Factors