Table1_The Potential Role of Epigenetic Mechanisms in the Development of Retinitis Pigmentosa and Related Photoreceptor Dystrophies.XLSX

Retinitis pigmentosa and related photoreceptor dystrophies (RPRPD) are rare retinal diseases caused by hereditary gene mutations resulting in photoreceptor death, followed by vision loss. While numerous genes involved in these diseases have been identified, many cases have still not been associated with any gene, indicating that new mechanisms may be involved in the pathogenesis of these photoreceptor dystrophies. Many genes associated with RPRPD regulate photoreceptor specification and maturation in the developing retina. Since retinal development begins with a population of equivalent, proliferating retinal progenitor cells (RPCs) having a specific “competence” in generating all types of retinal neurons, including cone and rod photoreceptors, we tested the epigenetic changes in promoters of genes required for photoreceptor development and genes associated with RPRPD during RPC differentiation into cone and rod photoreceptors. We found that promoters of many of these genes are epigenetically repressed in RPCs but have no epigenetic restrictions in photoreceptors. Our findings also suggest that DNA methylation as an epigenetic mark, and DNA demethylation as a process, are more important than other epigenetic marks or mechanisms in the pathogenesis of these diseases. Most notably, irregularities in the DNA demethylation process during the RPC-to-photoreceptor transition may significantly contribute to retinitis pigmentosa (RP) pathogenesis since genes with hypermethylated promoters in RPCs account for at least 40% of autosomal recessive RP cases and at least 30% of autosomal dominant RP cases. Thus, we proposed an epigenetic model according to which unsuccessful demethylation of regulatory sequences (e.g., promoters, enhancers) of genes required for photoreceptor development, maturation, and function during the RPC-to-photoreceptor transition may reduce or even eliminate their activity, leading to RPRPD without any inheritable mutations in these genes.

色素性视网膜炎及相关光感受器营养不良症（Retinitis Pigmentosa and related photoreceptor dystrophies, RPRPD）是一类罕见的遗传性视网膜疾病，由遗传性基因突变引发光感受器死亡，继而导致视力丧失。尽管目前已鉴定出诸多与这类疾病相关的致病基因，但仍有大量病例未关联到任何已知基因，提示此类光感受器营养不良症的发病机制或存在未被揭示的新途径。许多与RPRPD相关的基因，在视网膜发育过程中调控光感受器的特化与成熟。由于视网膜发育起始于一群同质化且具备增殖能力的视网膜祖细胞（Retinal Progenitor Cells, RPCs），这类细胞具备生成包括视锥、视杆光感受器在内的所有视网膜神经元的特定潜能，因此我们检测了在视网膜祖细胞分化为视锥、视杆光感受器的过程中，光感受器发育必需基因以及与RPRPD相关基因的启动子区域的表观遗传变化。研究发现，这类基因中的多数启动子在视网膜祖细胞中处于表观遗传抑制状态，但在光感受器中则无表观遗传限制。本研究结果同时表明，作为表观遗传标记的DNA甲基化，以及作为表观遗传过程的DNA去甲基化，在这类疾病的发病机制中比其他表观遗传标记或机制发挥更为关键的作用。尤为值得注意的是，在视网膜祖细胞向光感受器转化的过程中，DNA去甲基化过程的异常可能会显著促进色素性视网膜炎（Retinitis Pigmentosa, RP）的发病：在视网膜祖细胞中启动子呈高甲基化状态的基因，至少占常染色体隐性RP病例的40%、常染色体显性RP病例的30%以上。据此，我们提出了一套表观遗传模型：在视网膜祖细胞向光感受器转化的过程中，若光感受器发育、成熟及功能必需基因的调控序列（如启动子、增强子）未能成功发生去甲基化，将会降低甚至完全丧失其活性，进而引发RPRPD，而此类病例中并不存在这些基因的可遗传突变。