The Dynamic Epigenetic Landscape of the Retina During Development, Reprogramming, and Tumorigenesis

• Published in: Neuron (Cambridge, Mass.) Vol. 94; no. 3; pp. 550 - 568.e10
• Main Authors: Aldiri, Issam, Xu, Beisi, Wang, Lu, Chen, Xiang, Hiler, Daniel, Griffiths, Lyra, Valentine, Marc, Shirinifard, Abbas, Thiagarajan, Suresh, Sablauer, Andras, Barabas, Marie-Elizabeth, Zhang, Jiakun, Johnson, Dianna, Frase, Sharon, Zhou, Xin, Easton, John, Zhang, Jinghui, Mardis, Elaine R., Wilson, Richard K., Downing, James R., Dyer, Michael A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-05-2017; Elsevier Limited
• Subjects: Adolescents; Adrenal glands; Amacrine cells; Animals; Animals, Genetically Modified; Assemblies; Bioinformatics; Bone growth; Cancer; Carcinogenesis - genetics; Cell cycle; Cell death; Cell Differentiation - genetics; Cellular Reprogramming - genetics; Central nervous system; Children; Deoxyribonucleic acid; Developmental stages; Disease Models, Animal; DNA; DNA methylation; DNA Methylation - genetics; Embryos; Epigenesis, Genetic; epigenetic memory; Epigenetics; Gene expression; Gene silencing; Genomes; Histone Code - genetics; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Inhibitory postsynaptic potentials; iPSCs; Mice; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; Neural stem cells; Neurogenesis; Neurons; Nucleotide sequence; Origins; Photoreceptors; Pluripotency; Retina; Retina - embryology; Retina - metabolism; retinal development; Retinal Rod Photoreceptor Cells - cytology; Retinoblastoma; Retinoblastoma - genetics; Retinoblastoma Protein - genetics; Retinogenesis; Ribonucleic acid; RNA; rod photoreceptors; Stem cells; Sympathetic nervous system; Transcription factors; Tumors; iPSCs; retinoblastoma; rod photoreceptors; DNA methylation; retinal development; epigenetics; epigenetic memory
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2017.04.022

In the developing retina, multipotent neural progenitors undergo unidirectional differentiation in a precise spatiotemporal order. Here we profile the epigenetic and transcriptional changes that occur during retinogenesis 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 super-enhancers and showed that most epigenetic changes are conserved in humans and mice. To determine how the epigenome changes during tumorigenesis and reprogramming, we performed integrated epigenetic analysis of murine and human retinoblastomas and induced pluripotent stem cells (iPSCs) derived from murine rod photoreceptors. The retinoblastoma epigenome mapped to the developmental stage when retinal progenitors switch from neurogenic to terminal patterns of cell division. The epigenome of retinoblastomas was more similar to that of the normal retina than that of retina-derived iPSCs, and we identified retina-specific epigenetic memory.
•Changes in histone modifications were more prominent than those in DNA methylation•Epigenetic changes were more prevalent at differentiation genes than progenitors•The retinoblastoma epigenome resembles the retina at a developmental transition•Histone modifications are important for neuronal epigenetic memory in iPSCs
Aldiri, Xu, and colleagues show in this article how the epigenome of the mouse and human retina changes during development in coordination with transcriptional programs. They also relate those developmental changes to retinoblastoma and epigenetic memory in retina-derived iPSCs.