HISTONE DEMETHYLATION BY JHDM1D REGULATES PHOTORECEPTOR GENERATION IN XENOPUS RETINA

The histone demethylase JHDM1D, also known as KDM7 and KIAA1718, catalyzes demethylation of both mono- or dimethylated H3K9 and H3K27, epigenetic marks associated with transcription repression. Although this chromatin modifier has been shown to control neural induction and differentiation, its role in retinal development remains unexplored. In this study, we address the retinal function of JHDM1D taking advantage of specific features of the Xenopus laevis model system. JHDM1D is expressed in the eye field and in retinal progenitors of optic vesicles and cups. JHDM1D overexpression in the early eye field does not significantly affect the retinal expression of markers of cell proliferation and differentiation or the expression of retinal progenitors markers. However, when JHDM1D is injected in a 16-cell stage blastomere fated to give rise partially to the retina, the generated retinal clones display an increase of photoreceptors and a decrease of bipolar cells, compared to control GFP injected embryos. Late overexpression, obtained by lipofecting retinal precursors of optic vesicles with JHDM1D cDNA, yields the same results. Furthermore, immunostaining with a rod-specific antibody shows that JHDM1D overexpression leads to a significant increase in rod-to-cone ratio. Intriguingly, JHDM1D knockdown also leads to an increase of photoreceptors, although without changing the rod-to-cone ratio. These results suggest that the balance between methylated and demethylated H3K9 and H3K27 controlled by JHDM1D is a crucial component of a histone code leading to photoreceptor specification. We are currently assaying the functional interactions between JHDM1D and JMJD3, a histone demethylase that removes a methyl group from trimethylated H3K27, thus providing further substrates for JHDM1D.