title: Regulation of alphaA-crystallin via Pax6, c-Maf, CREB and a broad domain of lens-specific chromatin.
abstract: 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.
authors: Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Ying
authors: Y
authors: Yang
authors: Tomás
authors: T
authors: Stopka
authors: Nady
authors: N
authors: Golestaneh
authors: Yan
authors: Y
authors: Wang
authors: Kongming
authors: K
authors: Wu
authors: Anping
authors: A
authors: Li
authors: Bharesh K
authors: BK
authors: Chauhan
authors: Chun Y
authors: CY
authors: Gao
authors: Kveta
authors: K
authors: Cveklová
authors: Melinda K
authors: MK
authors: Duncan
authors: Richard G
authors: RG
authors: Pestell
authors: Ana B
authors: AB
authors: Chepelinsky
authors: Arthur I
authors: AI
authors: Skoultchi
authors: Ales
authors: A
authors: Cvekl