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. Examination of 8 different histone modifications and 3 transcription factors, transcriptome, DNA methylation in 23 cell types

与中枢神经系统的诸多其他区域一样，在发育中的视网膜内，多能神经前体细胞(multipotent neural progenitor cells)会经历单向的动态变化，以精准的时空时序生成分化细胞。本研究对小鼠与人类视网膜发育过程中发生的表观遗传与转录组变化进行了全景式分析。尽管在视网膜发生过程中，部分前体细胞基因与细胞周期基因会通过表观遗传机制被沉默，但最显著的变化是细胞类型特异性分化程序的去抑制激活。我们鉴定出了发育阶段特异性的超级增强子(superenhancers)，并证实小鼠视网膜发育过程中的绝大多数表观遗传变化在人类视网膜中均具有保守性。为探明表观基因组在肿瘤发生与重编程过程中的变化规律，我们对小鼠及人类视网膜母细胞瘤(retinoblastomas)，以及源自小鼠视杆光感受器(rod photoreceptors)的诱导多能干细胞(induced pluripotent stem cells, iPSCs)开展了相同的整合表观遗传分析。视网膜母细胞瘤的表观基因组特征匹配于视网膜前体细胞从神经发生模式切换至终末细胞分裂模式的发育阶段，且小鼠视网膜母细胞瘤的发育起始时间早于人类肿瘤。相较于视网膜来源的诱导多能干细胞，视网膜母细胞瘤的表观基因组与正常视网膜的相似性显著更高，但我们仍可鉴定出视网膜特异性的表观遗传记忆。综上，本研究数据全面揭示了神经发生过程中动态变化的表观基因组特征，及其与发育性肿瘤以及神经元来源诱导多能干细胞中表观遗传记忆的关联机制。本研究共检测了23种细胞类型中的8种不同组蛋白修饰、3种转录因子、转录组以及DNA甲基化水平。