Laboratory of Neurogenetics, Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre of the Polish Academy of Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland.
Central Forensic Laboratory of the Police, 7 Aleje Ujazdowskie Street, 00-583 Warsaw, Poland.
Oxid Med Cell Longev. 2018 Apr 4;2018:6918797. doi: 10.1155/2018/6918797. eCollection 2018.
Epigenetic mechanisms play an important role in the development and progression of various neurodegenerative diseases. Abnormal methylation of numerous genes responsible for regulation of transcription, DNA replication, and apoptosis has been linked to Alzheimer's disease (AD) pathology. We have recently performed whole transcriptome profiling of familial early-onset Alzheimer's disease (fEOAD) patient-derived fibroblasts. On this basis, we demonstrated a strong dysregulation of cell cycle checkpoints and DNA damage response (DDR) in both fibroblasts and reprogrammed neurons. Here, we show that the aging-correlated hypermethylation of and genes associates with abnormalities in DNA repair and cell cycle control in fEOAD. Based on the resulting transcriptome networks, we found that the hypermethylation of might be associated with epigenetic regulation of the chromatin organization and mRNA processing followed by hypermethylation of likely associated with the G2/M cell cycle phase and p53 role in DNA repair with BRCA1 protein as the key player. We propose that the hypermethylation of could constitute a superior epigenetic mechanism for hypermethylation. The methylation status of both genes affects genome stability and might contribute to proapoptotic signaling in AD. Since this study combines data obtained from various tissues from AD patients, it reinforces the view that the genetic methylation status in the blood may be a valuable predictor of molecular processes occurring in affected tissues. Further research is necessary to define a detailed role of TRIM59 and KLF4 in neurodegeneration of neurons.
表观遗传机制在各种神经退行性疾病的发展和进展中起着重要作用。许多负责转录调控、DNA 复制和细胞凋亡的基因的异常甲基化与阿尔茨海默病 (AD) 病理学有关。我们最近对家族性早发性阿尔茨海默病 (fEOAD) 患者来源的成纤维细胞进行了全转录组谱分析。在此基础上，我们证明了成纤维细胞和重编程神经元中的细胞周期检查点和 DNA 损伤反应 (DDR) 都出现了强烈失调。在这里，我们表明 和 基因的衰老相关高甲基化与 fEOAD 中的 DNA 修复和细胞周期控制异常有关。基于产生的转录组网络，我们发现 的高甲基化可能与染色质组织和 mRNA 处理的表观遗传调控有关，随后 的高甲基化可能与 G2/M 细胞周期阶段和 p53 在 DNA 修复中的作用有关，BRCA1 蛋白是关键参与者。我们提出， 的高甲基化可能构成 高甲基化的优越表观遗传机制。这两个基因的甲基化状态影响基因组稳定性，并可能导致 AD 中的促凋亡信号。由于本研究结合了来自 AD 患者不同组织的数据，因此它进一步证实了血液中的遗传甲基化状态可能是受影响组织中发生的分子过程的有价值的预测指标。需要进一步的研究来确定 TRIM59 和 KLF4 在神经元神经退行性变中的详细作用。
