Regulation of [alpha]A-crystallin via Pax6, c-Maf, CREB and a broad domain of lens-specific chromatin

• Published in: The EMBO journal 2006-05, Vol.25 (10), p.2107-2118
• Main Authors: Yang, Ying, Stopka, Tomás, Golestaneh, Nady, Wang, Yan, Wu, Kongming, Li, Anping, Chauhan, Bharesh K, Gao, Chun Y, Cveklová, Kveta, Duncan, Melinda K, Pestell, Richard G, Chepelinsky, Ana B, Skoultchi, Arthur I, Cvekl, Ales
• Format: Article
• Language: English
• Subjects: Binding sites; Cell differentiation; Chromatin; Enzymes; Fibers; Gene expression; Genes; Mammals; Signal transduction
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/sj.emboj.7601114

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.