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Akira Murakami, Toshiro Iwagwa, Sumiko Watanabe; Roles of HistoneH3K27 tri-methylation for differentiation of subsets of retinal cells. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1474.
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© ARVO (1962-2015); The Authors (2016-present)
Cell differentiation and maintenance are regulated by transcription factor as well as epigenetic network. We aimed to reveal roles of Histone H3K27 tri-methylation (H3K27me3) for retinal development.
Expression patterns of Jmjd3, which is a specific de-methylase of H3K27me3, and Ezh2 and Ezh1, which are specific methyltransferases of H3K27, were examined by immunostaining and in situ hybridization. Retina specific knockout mice of Jmjd3 (Jmjd3-CKO) and Ezh2 (Ezh2-CKO) were generated by cre/flox system using Dkk3-cre mice. Retinal development was examined by immunostaining using retinal subtype markers, and molecular signature of the mice was examined by qPCR, RNAseq, and ChIP-qPCR.
Ezh2 was strongly and widely expressed in retinal progenitor cells and then, its expression declined rapidly after birth, and Ezh1 was expressed transiently and weakly in postnatal retina. Jmjd3 was weakly expressed in ganglion cell layer (GCL) during embryonic stage, and transiently but strongly expressed in GCL and inner nuclear layer at around P5 to P8, then disappeared. Retina specific Ezh2-CKO showed microphthalmia, but slight increased population of Rod-ON-bipolar cells was observed. De-repression of Ink4a/Arf expression was observed as previously observed other tissues, and proliferation of postnatal progenitor cells was slightly impaired. Retina specific knockout of Jmjd3 in mouse resulted in failure of development of retinal ganglion cells (RGC) and subsets of Rod-ON-bipolar cells. ERG recording patterns were in accordance with the phenotype of the mice that is a lack of Rod-ON-bipolar cells. RNA-seq and CHIP-qPCR of Jmjd3-CKO retina and control indicated that several genes including Vsx1 and Bhlhb4 may be targets of H3K27me3 in retina.
H3K27me3 plays pivotal roles for differentiation of Rod-ON-bipolar and RGC through de-methylation of H3K27me3 at loci of genes responsible for differentiation and maturation of these subsets of retinal cells, such as Bhlhb4, and Vsx1 by spatio-temporally specific expression of Jmjd3.
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