title: Regulation of Retinal Development via the Epigenetic Modification of Histone H3.
abstract: We are interested in the roles of epigenetic mechanisms in retinal development. By ChIP-qPCR using whole retinal extracts at various developmental stages, we found that the levels of methylation of histones H3K27 and H3K4 and acetylation of histone H3 at specific loci in various genes, which play critical roles in retinal proliferation and differentiation, changed dramatically during retinal development. We next focused on the roles of H3K27 trimethylation in retinal development. Ezh1 and Ezh2 are methyltransferases that act on H3K27, while Jmjd3 and Utx are demethylases. We found that Ezh2 and Jmjd3 were mainly expressed during retinal development, and a loss-of-function of these genes revealed a role for H3K27me3 in the maturation of subsets of bipolar cells. Furthermore, Ezh2 and Jmjd3 regulate H3K27 trimethylation at specific loci within Bhlhb4 and Vsx1, which play critical roles in the differentiation of subsets of bipolar cells. Utx is expressed weakly in retina, and the down-regulation of Utx by sh-RNA in retinal explants suggested that Utx also participates in the maturation of bipolar cells. Ezh1 is expressed weakly in postnatal retina, and the phenotype of Ezh2-knockout retina suggested that Ezh1 plays a role in the methylation of H3K27 in the late phase of retinal differentiation. Taken together, we found that these four genes, which exhibit temporally and spatially unique expression patterns during retinal development, play critical roles in the differentiation of retinal subsets through the regulation of histone H3K27 methylation at critical genetic loci.
authors.affiliation: Division of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan. sumiko@ims.u-tokyo.ac.jp.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Ophthalmology, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Murakami
mesh_terms: D000818:Animals; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008813:Mice, Inbred ICR; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012160:Retina / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D006657:Histones; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C111778:Utx protein, mouse; C523761:Kdm6b protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498408:Ezh1 protein, mouse; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D008239:Lysine
keywords: Bipolar cells; ChIP-qPCR; Epigenetics modification; Histone H3 acetylation; Histone H3 methylation; Retinal development; Rod photoreceptors