Table2_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感光细胞营养不良症（Retinitis pigmentosa and related photoreceptor dystrophies, RPRPD）是一类罕见的视网膜疾病，由遗传性基因突变引发感光细胞死亡，进而导致视力丧失。尽管目前已鉴定出众多与这类疾病相关的基因，但仍有大量病例未发现明确的关联基因，这提示此类感光细胞营养不良症的发病机制中可能存在尚未阐明的新机制。诸多与RPRPD相关的基因，在视网膜发育过程中调控感光细胞的特化与成熟。由于视网膜发育起始于一群均一的、具有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、视杆感光细胞在内的所有视网膜神经元的特定潜能，本研究检测了在视网膜祖细胞向视锥、视杆感光细胞分化的过程中，感光细胞发育必需基因以及与RPRPD相关基因的启动子区域表观遗传变化。我们发现，这类基因中的多数启动子区域在视网膜祖细胞中处于表观遗传抑制状态，而在感光细胞中则不存在表观遗传限制。本研究结果还提示，相较于其他表观遗传标记或调控机制，作为表观遗传标记的DNA甲基化，以及作为调控过程的DNA去甲基化，在这类疾病的发病机制中发挥着更为关键的作用。尤为值得关注的是，在视网膜祖细胞向感光细胞转化的过程中，DNA去甲基化过程的异常可能是色素性视网膜炎（Retinitis pigmentosa, RP）发病的重要诱因：在视网膜祖细胞中启动子区域呈高甲基化状态的相关基因，至少占到常染色体隐性RP病例的40%，以及常染色体显性RP病例的30%。据此，我们提出了一项表观遗传模型：在视网膜祖细胞向感光细胞转化的过程中，感光细胞发育、成熟及功能必需基因的调控序列（如启动子、增强子）未能顺利完成去甲基化，可能会降低甚至完全丧失这些基因的活性，进而在这些基因不存在遗传性突变的情况下引发RPRPD。