Department of Neuroscience, Section of Neurosurgery, Uppsala University, Uppsala, Sweden.
Division of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
J Neurotrauma. 2021 Jun 15;38(12):1679-1688. doi: 10.1089/neu.2020.7283. Epub 2021 Jan 8.
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 (), microtubule associated protein tau (), neurofilament heavy (), neurofilament medium (), and neurofilament light (), 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 , , , and genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the 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.
创伤性脑损伤（TBI）是神经退行性疾病和痴呆的既定危险因素。表观遗传修饰，如 DNA 甲基化，可能会在不改变 DNA 序列的情况下，响应环境因素改变基因的表达。我们假设，在受伤的人脑内可能会发生 DNA 甲基化改变，并可能与 TBI 后的神经退行性过程有关。我们分析了 17 例严重 TBI 患者新鲜手术切除的人脑组织和 19 例特发性正常压力脑积水（iNPH）患者脑活检样本中与神经退行性相关的基因的 DNA 甲基化状态，例如淀粉样前体蛋白（）、微管相关蛋白 tau（）、神经丝重链（）、神经丝中间链（）和神经丝轻链（）。我们还进行了一项表观基因组关联研究（EWAS），将 TBI 患者与 iNPH 对照进行比较。TBI 导致 、 、 和 基因中的 38 个 CpG 位点发生差异甲基化。在 top20 差异甲基化的 CpG 位点中，有 11 个位于 基因中。此外，评估 828888 个 CpG 位点的 EWAS 显示，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有 308 个 CpG 位点发生差异甲基化。这些初步发现提供了受伤人脑内 DNA 甲基化组改变的首个证据，可能与 TBI 相关的神经退行性疾病有关。
