Latent epigenetic programs in Müller glia contribute to stress and disease response in the retina

Previous studies have demonstrated the dynamic changes in chromatin structure during retinal development correlate with changes in gene expression. However, those studies lack cellular resolution. Here, we integrate single-cell RNA Sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin Sequencing (scATAC-seq) with bulk data to identify cell-type-specific changes in chromatin structure during human and murine development. Although promoter activity is correlated with chromatin accessibility, we discovered several hundred genes that were transcriptionally silent but had accessible chromatin at their promoters. Most of those silent/accessible gene promoters were in Müller glial cells, which function to maintain retinal homeostasis and respond to stress, injury, or disease. We refer to these as "pliancy genes" because they allow the Müller glia to rapidly change their gene expression and cellular state in response to retinal insults. The Müller glial cell pliancy program is established during development, and we demonstrate that pliancy genes are important for regulating inflammation in the murine retina in vivo.

Müller glia; chemokines; epigenetics; inflammation; pliancy; regeneration; retina; retinopathy; scRNA-seq.