Transcriptome and DNA methylome signatures associated with retinal Müller glia development, injury response, and aging

Abstract

PURPOSE. The purpose of this study was to systematically characterize and correlate the transcriptome and DNA methylome signatures of mouse Müller cells that may underlie the development, physiological functions, and regeneration capacity of these cells. METHODS. Mouse Müller cells under normal, injury, and aging conditions were sorted from Müller cell–specific green fluorescent protein (GFP)-expressing mice. RNA sequencing was used to sequence transcriptomes, and reduced representation bisulfite sequencing was used to sequence DNA methylomes. Various bioinformatics tools were used to compare and correlate the transcriptomes and DNA methylomes. RESULTS. Müller cells express a distinct transcriptome that is in line with their retinal supporting roles and dormant retinogenic status. Injury changes the Müller cell transcriptome dramatically but fails to stimulate the cell cycle machinery and retinogenic factors to the states observed in early retinal progenitor cells (RPCs). Müller cells exhibit a less methylated genome than that of early RPCs, but most regulatory elements for Müller cell– and RPC-specific genes are similarly hypomethylated in both Müller cells and RPCs, except for a subset of Müller cell–specific functional genes. Aging only subtly affects the transcriptome and DNA methylome of Müller cells. CONCLUSIONS. Failure to reactivate the cell cycle machinery and retinogenic factors to necessary levels might be key barriers blocking Müller cells from entering an RPC-like regeneration state. DNA methylation might regulate the expression of a subset of Müller cell–specific functional genes during development but is likely not involved in restricting the regeneration activity of Müller cells.