Zinc finger protein 267 is up-regulated during the activation process of human hepatic stellate cells and functions as a negative transcriptional regulator of MMP-10.
Activation of hepatic stellate cells (HSCs) is the central event in the development of liver fibrosis and cirrhosis. The transdifferentiation process of quiescent into activated HSCs requires a complete reprogramming in gene expression, which is governed by modulation of transcriptional activators or repressors. Using microarray analysis to identify genes differentially expressed during the activation process of human HSCs, zinc finger protein 267 (ZNF267) mRNA was up-regulated in activated HSCs and in cirrhotic human liver. ZNF267 belongs to the family of Kruppel-like zinc fingers and contains a conserved KRAB (Kruppel associated box) A and B domain in the N-terminal part outside the C-terminal region of zinc fingers. ZNF267 constructs containing enhanced cyan fluorescence protein were constitutively localized in the nucleus. When fused to GAL4 DNA binding domain, full-length ZNF267 and all constructs encompassing KRAB A domain showed transcriptional repressor activity. Microarray analysis and RNase protection assays showed that ZNF267 represses MMP-10 gene expression, which was confirmed by reporter gene assays. Furthermore, ZNF267 binds to the MMP-10 promoter region as demonstrated by chromatin immunoprecipitation assays. In conclusion, our results suggest that ZNF267 as a negative transcriptional regulator of MMP-10 might promote liver fibrogenesis through alteration of matrix degradation in vivo.
Schnabl
Bernd
B
Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. bs2278@columbia.edu
Hu
Kanghong
K
Mühlbauer
Marcus
M
Hellerbrand
Claus
C
Stefanovic
Branko
B
Brenner
David A
DA
Schölmerich
Jürgen
J
D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics; D053506:Matrix Metalloproteinase 10; D008666:Metalloendopeptidases / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C502002:ZNF267 protein, human; D008666:Metalloendopeptidases; D053506:Matrix Metalloproteinase 10; D006655:Histone Deacetylases