DNA 甲基化的读者，MBD 家族作为潜在的治疗靶点。
Readers of DNA methylation, the MBD family as potential therapeutic targets.
机构信息
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, United States; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, United States.
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
出版信息
Pharmacol Ther. 2018 Apr;184:98-111. doi: 10.1016/j.pharmthera.2017.11.002. Epub 2017 Nov 8.
DNA methylation represents a fundamental epigenetic modification that regulates chromatin architecture and gene transcription. Many diseases, including cancer, show aberrant methylation patterns that contribute to the disease phenotype. DNA methylation inhibitors have been used to block methylation dependent gene silencing to treat hematopoietic neoplasms and to restore expression of developmentally silenced genes. However, these inhibitors disrupt methylation globally and show significant off-target toxicities. As an alternative approach, we have been studying readers of DNA methylation, the 5-methylcytosine binding domain family of proteins, as potential therapeutic targets to restore expression of aberrantly and developmentally methylated and silenced genes. In this review, we discuss the role of DNA methylation in gene regulation and cancer development, the structure and function of the 5-methylcytosine binding domain family of proteins, and the possibility of targeting the complexes these proteins form to treat human disease.
DNA 甲基化是一种重要的表观遗传修饰，它调节染色质结构和基因转录。许多疾病，包括癌症，都表现出异常的甲基化模式，这些模式导致了疾病表型。DNA 甲基化抑制剂已被用于阻断依赖甲基化的基因沉默，以治疗造血肿瘤，并恢复发育性沉默基因的表达。然而，这些抑制剂会全局地破坏甲基化，并表现出显著的脱靶毒性。作为一种替代方法，我们一直在研究 DNA 甲基化的读取器，即 5-甲基胞嘧啶结合域家族蛋白，作为恢复异常和发育性甲基化和沉默基因表达的潜在治疗靶点。在这篇综述中，我们讨论了 DNA 甲基化在基因调控和癌症发展中的作用、5-甲基胞嘧啶结合域家族蛋白的结构和功能，以及靶向这些蛋白形成的复合物治疗人类疾病的可能性。
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