Epigenetic Signatures of the Genes Downregulated During Retina Development

We characterized two groups of genes that participate in embryonic stages of retinal development by analyzing mouse retinal temporal whole-genome datasets for two histone modifications, H3K4me2 and H3K27me3, and DNase I hypersensitive sites (DHS). Epigenetic profiles for genes belonging to the first group demonstrate the disappearance of DHS and the active chromatin marker H3K4me2 from the gene body during development, and a dramatic increase in the accumulation of a chromatin inhibitory marker, H3K27me3. Using epigenetic profiles, this group could be easily divided into subgroups of early- and late-embryonic-stage genes of retinal development that mostly work as pioneering factors for early stages or as transcriptional factors for later stages. Epigenetic profiles for the second, smaller group were characterized by a decrease in the active marker H3K4me2 that was not accompanied by an increase in the inhibitory marker H3K27me3. Most members of this small group could be functionally annotated as transcriptional or proliferation inhibitors, but this group did not show specificity in DAVID, STRING, and IPA analyses. However, based on a literature search, 14 genes and two microRNAs were linked to the Smad/TGF-b pathway. By using ex vivo differentiation of mouse embryonic stem cells (ESCs), we have shown that two members of this group, Pmepa1 and Skil, participate in the early stages of mouse retina development in Activin signaling via the Smad2/3 pathway. This is the first time Pmepa1 and Skil have been proposed as candidate genes to regulate retinal development. Together, the results suggest that expression of functionally related groups of genes can be downregulated by changes in DNA accessibility caused by specific epigenetic changes.