The Dynamic Epigenetic Landscape of the Retina During Development, Reprogramming, and Tumorigenesis [ATAC-Seq_Mm]

In the developing retina, as in many other regions of the central nervous system, multipotent neural progenitor cells undergo unidirectional changes to produce differentiated cells in a precise spatiotemporal order. Here we profile the epigenetic and transcriptional changes that occur during retinal development in mice and humans. Although some progenitor genes and cell cycle genes were epigenetically silenced during retinogenesis, the most dramatic change was derepression of cell type–specific differentiation programs. We identified developmental stage–specific superenhancers and showed that the majority of epigenetic changes during murine retinal development are conserved in the human retina. To determine how the epigenome changes during tumorigenesis and reprogramming, we performed the same integrated epigenetic analysis of murine and human retinoblastomas and iPSCs derived from murine rod photoreceptors. The retinoblastoma epigenome mapped to the developmental stage when retinal progenitors switch from a neurogenic to a terminal pattern of cell division and murine retinoblastomas initiate earlier in development than human tumors. The epigenome of retinoblastomas was far more similar to that of normal retina than was the epigenome of retinal-derived iPSCs but we were able to identify retinal specific epigenetic memory. Together, these data provide an in depth view of the dynamic epigenome during neurogenesis and how that relates to developmental tumors and epigenetic memory in iPSCs produced from neurons. Overall design: Examination of 8 different histone modifications and 3 transcription factors, transcriptome, DNA methylation in 23 cell types