Open AccessThe HNF-4/HNF-1α transactivation cascade regulates gene activity and chromatin structure of the human serine protease inhibitor gene cluster at 14q32.1
Author(s) -
Pierre Rollini,
R. E. K. Fournier
Publication year - 1999
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.96.18.10308
Subject(s) - chromatin , biology , microbiology and biotechnology , chromatin remodeling , hypersensitive site , chia pet , gene , transcription factor , transactivation , ccaat enhancer binding proteins , dnase i hypersensitive site , bivalent chromatin , locus control region , chromodomain , regulation of gene expression , gene expression , promoter , nuclear protein , genetics , helicase , rna
Hepatocyte-specific expression of the α1-antitrypsin (α1AT) gene requires the activities of two liver-enriched transactivators, hepatocyte nuclear factors 1α and 4 (HNF-1α and HNF-4). The α1AT gene maps to a region of human chromosome 14q32.1 that includes a related serine protease inhibitor (serpin) gene encoding corticosteroid-binding globulin (CBG), and the chromatin organization of this ≈130-kb region, as defined by DNase I-hypersensitive sites, has been described. Microcell transfer of human chromosome 14 from fibroblasts to rat hepatoma cells results in activation of α1AT and CBG transcription and chromatin reorganization of the entire locus. To assess the roles of HNF-1α and HNF-4 in gene activation and chromatin remodeling, we transferred human chromosome 14 from fibroblasts to rat hepatoma cell variants that are deficient in expression of HNF-1α and HNF-4. The variant cells failed to activate either α1AT or CBG transcription, and chromatin remodeling failed to occur. However, α1AT and CBG transcription could be rescued by transfecting the cells with expression plasmids encoding HNF-1α or HNF-4. In these transfectants, the chromatin structure of the entire α1AT/CBG locus was reorganized to an expressing cell-typical state. Thus, HNF-1α and HNF-4 control both chromatin structure and gene activity of two cell-specific genes within the serpin gene cluster at 14q32.1.