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Differential DNA Methylation of the Genes for Amyloid Precursor Protein, Tau, and Neurofilaments in Human Traumatic Brain Injury
Journal of Neurotrauma ( IF 3.9 ) Pub Date : 2021-05-26 , DOI: 10.1089/neu.2020.7283
Sami Abu Hamdeh 1 , Diana-Maria Ciuculete 2 , Daniil Sarkisyan 3 , Georgy Bakalkin 3 , Martin Ingelsson 4 , Helgi B Schiöth 2, 5 , Niklas Marklund 6
Affiliation  

Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI. The DNA methylation status of genes related to neurodegeneration; for example, amyloid beta precursor protein (APP), microtubule associated protein tau (MAPT), neurofilament heavy (NEFH), neurofilament medium (NEFM), and neurofilament light (NEFL), was analyzed in fresh, surgically resected human brain tissue from 17 severe TBI patients and compared with brain biopsy samples from 19 patients with idiopathic normal pressure hydrocephalus (iNPH). We also performed an epigenome-wide association study (EWAS) comparing TBI patients with iNPH controls. Thirty-eight CpG sites in the APP, MAPT, NEFH, and NEFL genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the APP gene. In addition, the EWAS evaluating 828,888 CpG sites revealed 308 differentially methylated CpG sites in genes related to cellular/anatomical structure development, cell differentiation, and anatomical morphogenesis. These preliminary findings provide the first evidence of an altered DNA methylome in the injured human brain, and may have implications for the neurodegenerative disorders associated with TBI.

中文翻译:

人类创伤性脑损伤中淀粉样前体蛋白、Tau 和神经丝基因的差异 DNA 甲基化

创伤性脑损伤 (TBI) 是神经退行性疾病和痴呆症的既定风险因素。表观遗传修饰,例如 DNA 甲基化,可能会改变基因的表达,而不改变 DNA 序列以响应环境因素。我们假设 DNA 甲基化变化可能发生在受伤的人脑中,并与 TBI 的神经退行性后果有关。与神经退行性变相关基因的 DNA 甲基化状态;例如,β淀粉样蛋白前体蛋白 ( APP )、微管相关蛋白 tau ( MAPT )、重神经丝 ( NEFH )、中神经丝 ( NEFM ) 和轻神经丝 ( NEFL )),对来自 17 名严重 TBI 患者的新鲜、手术切除的人脑组织进行了分析,并与来自 19 名特发性正常压力脑积水 (iNPH) 患者的脑活检样本进行了比较。我们还进行了一项表观基因组关联研究 (EWAS),将 TBI 患者与 iNPH 对照进行了比较。APPMAPTNEFHNEFL基因中的 38 个 CpG 位点被 TBI 差异甲基化。在前 20 个差异甲基化 CpG 位点中,有 11 个在APP中基因。此外,评估 828,888 个 CpG 位点的 EWAS 揭示了与细胞/解剖结构发育、细胞分化和解剖形态发生相关的基因中的 308 个差异甲基化 CpG 位点。这些初步发现提供了受伤人脑中 DNA 甲基化组改变的第一个证据,并可能对与 TBI 相关的神经退行性疾病产生影响。
更新日期:2021-06-08
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