Regulation of αA-crystallin via Pax6, c-Maf, CREB and a broad domain of lens-specific chromatin

Ying Yang, Tomáš Stopka, Nady Golestaneh, Yan Wang, Kongming Wu, Anping Li, Bharesh K. Chauhan, Chun Y. Gao, Květa Cveklová, Melinda K. Duncan, Richard G. Pestell, Ana B. Chepelinsky, Arthur I. Skoultchi, Ales Cvekl

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Pax6 and c-Maf regulate multiple stages of mammalian lens development. Here, we identified novel distal control regions (DCRs) of the αA-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 αA-crystallin synthesis. A DCR1/αA-crystallin promoter (including DCR2) coupled with EGFP virtually recapitulated the expression pattern of αA-crystallin in lens epithelium and fibers. In contrast, the DCR3/αA/EGFP reporter was expressed only in 'late' lens fibers. Chromatin immunoprecipitations showed binding of Pax6 to DCR1 and the αA-crystallin promoter in lens chromatin and demonstrated that high levels of αA-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 αA-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 αA-crystallin during lens differentiation.

Original languageEnglish (US)
Pages (from-to)2107-2118
Number of pages12
JournalEMBO Journal
Volume25
Issue number10
DOIs
StatePublished - May 17 2006

Fingerprint

Crystallins
Lenses
Chromatin
Chromatin Assembly and Disassembly
Fibers
Chromatin Immunoprecipitation
Fibroblast Growth Factor 2
Enzymes
Reporter Genes
Gene expression
Histones
Cell Differentiation
Epithelium
Genes
Chemical activation
Gene Expression

Keywords

  • c-Maf
  • Chromatin remodeling
  • Histone acetylation and methylation
  • Lens differentiation
  • Pax6

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Regulation of αA-crystallin via Pax6, c-Maf, CREB and a broad domain of lens-specific chromatin. / Yang, Ying; Stopka, Tomáš; Golestaneh, Nady; Wang, Yan; Wu, Kongming; Li, Anping; Chauhan, Bharesh K.; Gao, Chun Y.; Cveklová, Květa; Duncan, Melinda K.; Pestell, Richard G.; Chepelinsky, Ana B.; Skoultchi, Arthur I.; Cvekl, Ales.

In: EMBO Journal, Vol. 25, No. 10, 17.05.2006, p. 2107-2118.

Research output: Contribution to journalArticle

Yang, Y, Stopka, T, Golestaneh, N, Wang, Y, Wu, K, Li, A, Chauhan, BK, Gao, CY, Cveklová, K, Duncan, MK, Pestell, RG, Chepelinsky, AB, Skoultchi, AI & Cvekl, A 2006, 'Regulation of αA-crystallin via Pax6, c-Maf, CREB and a broad domain of lens-specific chromatin', EMBO Journal, vol. 25, no. 10, pp. 2107-2118. https://doi.org/10.1038/sj.emboj.7601114
Yang, Ying ; Stopka, Tomáš ; Golestaneh, Nady ; Wang, Yan ; Wu, Kongming ; Li, Anping ; Chauhan, Bharesh K. ; Gao, Chun Y. ; Cveklová, Květa ; Duncan, Melinda K. ; Pestell, Richard G. ; Chepelinsky, Ana B. ; Skoultchi, Arthur I. ; Cvekl, Ales. / Regulation of αA-crystallin via Pax6, c-Maf, CREB and a broad domain of lens-specific chromatin. In: EMBO Journal. 2006 ; Vol. 25, No. 10. pp. 2107-2118.
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AU - Wang, Yan

AU - Wu, Kongming

AU - Li, Anping

AU - Chauhan, Bharesh K.

AU - Gao, Chun Y.

AU - Cveklová, Květa

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AU - Pestell, Richard G.

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AB - Pax6 and c-Maf regulate multiple stages of mammalian lens development. Here, we identified novel distal control regions (DCRs) of the αA-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 αA-crystallin synthesis. A DCR1/αA-crystallin promoter (including DCR2) coupled with EGFP virtually recapitulated the expression pattern of αA-crystallin in lens epithelium and fibers. In contrast, the DCR3/αA/EGFP reporter was expressed only in 'late' lens fibers. Chromatin immunoprecipitations showed binding of Pax6 to DCR1 and the αA-crystallin promoter in lens chromatin and demonstrated that high levels of αA-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 αA-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 αA-crystallin during lens differentiation.

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