Division of Cells, Organisms and Molecular Genetics, School of Life Sciences, University of Nottingham, Nottingham, UK.
Institute of Mental Health, Mental Health and Clinical Neurosciences Academic Unit, School of Medicine, University of Nottingham, Nottingham, UK.
Mol Neurobiol. 2023 Apr;60(4):2223-2235. doi: 10.1007/s12035-022-03195-6. Epub 2023 Jan 17.
Epigenetic processes have become increasingly relevant in understanding disease-modifying mechanisms. 5-Methylcytosine methylations of DNA (5mC) and RNA (mC) have functional transcriptional and RNA translational consequences and are tightly regulated by writer, reader and eraser effector proteins. To investigate the involvement of 5mC/5hmC and mC effector proteins contributing to the development of dementia neuropathology, RNA sequencing data of 31 effector proteins across four brain regions was examined in 56 aged non-affected and 51 Alzheimer's disease (AD) individuals obtained from the Aging, Dementia and Traumatic Brain Injury Study. Gene expression profiles were compared between AD and controls, between neuropathological Braak and CERAD scores and in individuals with a history of traumatic brain injury (TBI). We found an increase in the DNA methylation writers DNMT1, DNMT3A and DNMT3B messenger RNA (mRNA) and a decrease in the reader UHRF1 mRNA in AD samples across three brain regions whilst the DNA erasers GADD45B and AICDA showed changes in mRNA abundance within neuropathological load groupings. RNA methylation writers NSUN6 and NSUN7 showed significant expression differences with AD and, along with the reader ALYREF, differences in expression for neuropathologic ranking. A history of TBI was associated with a significant increase in the DNA readers ZBTB4 and MeCP2 (p < 0.05) and a decrease in NSUN6 (p < 0.001) mRNA. These findings implicate regulation of protein pathways disrupted in AD and TBI via multiple pre- and post-transcriptional mechanisms including potentially acting upon transfer RNAs, enhancer RNAs as well as nuclear-cytoplasmic shuttling and cytoplasmic translational control. The targeting of such processes provides new therapeutic avenues for neurodegenerative brain conditions.
表观遗传过程在理解疾病修饰机制方面变得越来越重要。DNA（5mC）和 RNA（mC）的 5-甲基胞嘧啶甲基化具有功能转录和 RNA 翻译后果，并受到写入器、读取器和橡皮擦效应蛋白的紧密调节。为了研究 5mC/5hmC 和 mC 效应蛋白在痴呆神经病理学发展中的作用，在 Aging, Dementia and Traumatic Brain Injury Study 中，对来自 56 名年龄未受影响和 51 名阿尔茨海默病（AD）个体的四个大脑区域的 31 种效应蛋白的 RNA 测序数据进行了检查。比较了 AD 和对照组之间、神经病理学 Braak 和 CERAD 评分之间以及有创伤性脑损伤（TBI）病史的个体之间的基因表达谱。我们发现，在三个大脑区域中，AD 样本中 DNA 甲基化写入器 DNMT1、DNMT3A 和 DNMT3B 的信使 RNA（mRNA）增加，而读取器 UHRF1 的 mRNA 减少，而 DNA 橡皮擦 GADD45B 和 AICDA 的 mRNA 丰度在神经病理学负荷分组中发生变化。RNA 甲基化写入器 NSUN6 和 NSUN7 的表达与 AD 存在显著差异，与 AD 相关的差异，以及与神经病理学分级相关的读者 ALYREF 的差异。TBI 病史与 DNA 读取器 ZBTB4 和 MeCP2 的显著增加相关（p < 0.05），与 NSUN6 的减少相关（p < 0.001）。这些发现表明，通过多种转录前和转录后机制，包括可能作用于转移 RNA、增强子 RNA 以及核质穿梭和细胞质翻译控制，调节 AD 和 TBI 中失调的蛋白途径。针对这些过程为神经退行性脑疾病提供了新的治疗途径。
