Regulation of alphaA-crystallin via Pax6, c-Maf, CREB and a broad domain of lens-specific chromatin.
Pax6 and c-Maf regulate multiple stages of mammalian lens development. Here, we identified novel distal control regions (DCRs) of the alphaA-crystallin gene, a marker of lens fiber cell differentiation induced by FGF-signaling. DCR1 stimulated reporter gene expression in primary lens explants treated with FGF2 linking FGF-signaling with alphaA-crystallin synthesis. A ... DCR1/alphaA-crystallin promoter (including DCR2) coupled with EGFP virtually recapitulated the expression pattern of alphaA-crystallin in lens epithelium and fibers. In contrast, the DCR3/alphaA/EGFP reporter was expressed only in 'late' lens fibers. Chromatin immunoprecipitations showed binding of Pax6 to DCR1 and the alphaA-crystallin promoter in lens chromatin and demonstrated that high levels of alphaA-crystallin expression correlate with increased binding of c-Maf and CREB to the promoter and of CREB to DCR3, a broad domain of histone H3K9-hyperacetylation extending from DCR1 to DCR3, and increased abundance of chromatin remodeling enzymes Brg1 and Snf2h at the alphaA-crystallin locus. Our data demonstrate a novel mechanism of Pax6, c-Maf and CREB function, through regulation of chromatin-remodeling enzymes, and suggest a multistage model for the activation of alphaA-crystallin during lens differentiation.
Mesh Terms:
Adenosine Triphosphatases, Amino Acid Sequence, Animals, Cell Differentiation, Chromatin, Chromosomal Proteins, Non-Histone, Cyclic AMP Response Element-Binding Protein, DNA Helicases, Eye Proteins, Gene Expression Regulation, Developmental, Genes, Reporter, Histones, Homeodomain Proteins, Humans, Lens, Crystalline, Mice, Mice, Transgenic, Molecular Sequence Data, Nuclear Proteins, Paired Box Transcription Factors, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-maf, RNA Polymerase II, Repressor Proteins, Signal Transduction, Tissue Culture Techniques, Transcription Factors, Transcription, Genetic, alpha-Crystallin A Chain
Adenosine Triphosphatases, Amino Acid Sequence, Animals, Cell Differentiation, Chromatin, Chromosomal Proteins, Non-Histone, Cyclic AMP Response Element-Binding Protein, DNA Helicases, Eye Proteins, Gene Expression Regulation, Developmental, Genes, Reporter, Histones, Homeodomain Proteins, Humans, Lens, Crystalline, Mice, Mice, Transgenic, Molecular Sequence Data, Nuclear Proteins, Paired Box Transcription Factors, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-maf, RNA Polymerase II, Repressor Proteins, Signal Transduction, Tissue Culture Techniques, Transcription Factors, Transcription, Genetic, alpha-Crystallin A Chain
EMBO J.
Date: May. 17, 2006
PubMed ID: 16675956
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