Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
Sci Rep. 2019 Mar 7;9(1):3860. doi: 10.1038/s41598-019-40262-w.
The epigenetic plasticity of amphibian retinal pigment epithelium (RPE) allows them to regenerate the entire retina, a trait known to be absent in mammals. In this study, we investigated the epigenetic plasticity of adult murine RPE to identify possible mechanisms that prevent mammalian RPE from regenerating retinal tissue. RPE were analyzed using microarray, ChIP-seq, and whole-genome bisulfite sequencing approaches. We found that the majority of key genes required for progenitor phenotypes were in a permissive chromatin state and unmethylated in RPE. We observed that the majority of non-photoreceptor genes had promoters in a repressive chromatin state, but these promoters were in unmethylated or low-methylated regions. Meanwhile, the majority of promoters for photoreceptor genes were found in a permissive chromatin state, but were highly-methylated. Methylome states of photoreceptor-related genes in adult RPE and embryonic retina (which mostly contain progenitors) were very similar. However, promoters of these genes were demethylated and activated during retinal development. Our data suggest that, epigenetically, adult murine RPE cells are a progenitor-like cell type. Most likely two mechanisms prevent adult RPE from reprogramming and differentiating into retinal neurons: 1) repressive chromatin in the promoter regions of non-photoreceptor retinal neuron genes; 2) highly-methylated promoters of photoreceptor-related genes.
两栖动物视网膜色素上皮 (RPE) 的表观遗传可塑性允许它们再生整个视网膜，这种特性已知在哺乳动物中不存在。在这项研究中，我们研究了成年鼠 RPE 的表观遗传可塑性，以确定可能阻止哺乳动物 RPE 再生视网膜组织的机制。使用微阵列、ChIP-seq 和全基因组亚硫酸氢盐测序方法对 RPE 进行了分析。我们发现，祖细胞表型所需的大多数关键基因处于允许染色质状态且在 RPE 中未甲基化。我们观察到，大多数非光感受器基因的启动子处于抑制性染色质状态，但这些启动子处于未甲基化或低甲基化区域。同时，大多数光感受器基因的启动子处于允许染色质状态，但高度甲基化。成年 RPE 和胚胎视网膜（主要包含祖细胞）中光感受器相关基因的甲基组状态非常相似。然而，这些基因的启动子在视网膜发育过程中被去甲基化和激活。我们的数据表明，从表观遗传学上讲，成年鼠 RPE 细胞是一种类似于祖细胞的细胞类型。很可能有两种机制阻止成年 RPE 重新编程并分化为视网膜神经元：1）非光感受器视网膜神经元基因启动子区域的抑制性染色质；2）光感受器相关基因的高度甲基化启动子。
