Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, United States of America; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, United States of America.
Cell Signal. 2020 Apr;68:109509. doi: 10.1016/j.cellsig.2019.109509. Epub 2019 Dec 23.
The role of genetic mutations in the development of polycystic kidney disease (PKD), such as alterations in PKD1 and PKD2 genes in autosomal dominant PKD (ADPKD), is well understood. However, the significance of epigenetic mechanisms in the progression of PKD remains unclear and is increasingly being investigated. The term of epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. Epigenetic information can be inherited during mammalian cell division to sustain phenotype specifically and physiologically responsive gene expression in the progeny cells. A multitude of functional studies of epigenetic modifiers and systematic genome-wide mapping of epigenetic marks reveal the importance of epigenomic mechanisms, including DNA methylation, histone/chromatin modifications and non-coding RNAs, in PKD pathologies. Deregulated proliferation is a characteristic feature of cystic renal epithelial cells. Moreover, defects in many of the molecules that regulate the cell cycle have been implicated in cyst formation and progression. Recent evidence suggests that alterations of DNA methylation and histone modifications on specific genes and the whole genome involved in cell cycle regulation and contribute to the pathogenesis of PKD. This review summarizes the recent advances of epigenetic mechanisms in PKD, which helps us to define the term of "PKD epigenetics" and group PKD epigenetic changes in three categories. In particularly, this review focuses on the interplay of epigenetic mechanisms with cell cycle regulation during normal cell cycle progression and cystic cell proliferation, and discusses the potential to detect and quantify DNA methylation from body fluids as diagnostic/prognostic biomarkers. Collectively, this review provides concepts and examples of epigenetics in cell cycle regulation to reveal a broad view of different aspects of epigenetics in biology and PKD, which may facilitate to identify possible novel therapeutic intervention points and to explore epigenetic biomarkers in PKD.
遗传突变在多囊肾病 (PKD) 的发展中的作用，例如常染色体显性多囊肾病 (ADPKD) 中 PKD1 和 PKD2 基因的改变，已经得到很好的理解。然而，表观遗传机制在 PKD 进展中的意义尚不清楚，并且越来越受到关注。表观遗传学一词描述了基因组功能中的一系列机制，这些机制不仅仅是由 DNA 序列本身引起的。表观遗传信息可以在哺乳动物细胞分裂过程中遗传，以维持后代细胞中特定的表型和生理反应性基因表达。对表观遗传修饰剂的大量功能研究和全基因组范围内的表观遗传标记作图揭示了表观基因组机制的重要性，包括 DNA 甲基化、组蛋白/染色质修饰和非编码 RNA，在 PKD 病理中。不受调节的增殖是囊性肾上皮细胞的一个特征。此外，许多调节细胞周期的分子的缺陷与囊肿的形成和进展有关。最近的证据表明，参与细胞周期调控的特定基因和整个基因组的 DNA 甲基化和组蛋白修饰的改变与 PKD 的发病机制有关。本文综述了表观遗传机制在 PKD 中的最新进展，有助于我们定义“PKD 表观遗传学”这一术语，并将 PKD 表观遗传变化分为三类。特别是，本文重点讨论了表观遗传机制与正常细胞周期进程和囊性细胞增殖过程中细胞周期调控的相互作用，并讨论了从体液中检测和定量 DNA 甲基化作为诊断/预后生物标志物的潜力。总的来说，本文综述了细胞周期调控中的表观遗传机制，揭示了生物学和 PKD 中不同表观遗传方面的广泛观点，这可能有助于确定可能的新的治疗干预点，并探索 PKD 中的表观遗传生物标志物。
