Cavalier Alyssa N, Smith Meghan E, McWilliams Gabriella T, McEntee Cali M, Bettcher Brianne M, Coughlan Christina, LaRocca Thomas J
Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, USA.
Columbine Health Systems Center for Healthy Aging, Colorado State University, Fort Collins, CO, USA.
Geroscience. 2025 Aug 8. doi: 10.1007/s11357-025-01765-9.
Aging and cognitive impairment increase the risk for Alzheimer's disease (AD), and growing evidence suggests that transposable elements (TEs) in the genome play a role in aging and AD. The mechanisms of TE dysregulation in this context are unclear, but one possibility is that epigenetic changes, including DNA hypomethylation and/or reduced chromatin structure, underlie age- and AD-related TE activity. Therefore, the purpose of the present study was to generate a resource for studying TE epigenetics in aging and AD, and to use it to determine if epigenetically dysregulated TEs are related to age/AD-relevant clinical outcomes. We performed RNA-seq on peripheral blood samples from 45 healthy older adults, mild cognitive impairment (MCI) and AD dementia patients, and we observed a pattern of undulating TE transcript expression with MCI and AD, similar to previous reports. We then used whole-genome bisulfite sequencing (WGBS) and transposase-accessible chromatin sequencing (ATAC-seq) to characterize global DNA methylation and chromatin accessibility in the same subjects. We found that most TEs that were enriched/dysregulated in our RNA-seq data with MCI and AD could be found within hypomethylated and chromatin-accessible regions of the genome. These TEs included several that have been directly linked to inflammation and disease in humans, and they were related to cognitive/functional diagnosis, age, and biomarkers of inflammation and neurodegeneration in the subjects we studied. Collectively, these findings are consistent with the idea that epigenetic alterations may contribute to TE transcript dysregulation that plays an important role in aging, cognitive decline, and AD.
衰老和认知障碍会增加患阿尔茨海默病（AD）的风险，越来越多的证据表明基因组中的转座元件（TEs）在衰老和AD中起作用。在这种情况下，TE失调的机制尚不清楚，但一种可能性是表观遗传变化，包括DNA低甲基化和/或染色质结构减少，是与年龄和AD相关的TE活性的基础。因此，本研究的目的是生成一个用于研究衰老和AD中TE表观遗传学的资源，并利用它来确定表观遗传失调的TEs是否与年龄/AD相关的临床结果有关。我们对45名健康老年人、轻度认知障碍（MCI）和AD痴呆患者的外周血样本进行了RNA测序，我们观察到MCI和AD患者的TE转录本表达呈波动模式，这与之前的报道相似。然后，我们使用全基因组亚硫酸氢盐测序（WGBS）和转座酶可及染色质测序（ATAC-seq）来表征同一受试者的全基因组DNA甲基化和染色质可及性。我们发现，在我们的RNA测序数据中，大多数在MCI和AD中富集/失调的TEs可以在基因组的低甲基化和染色质可及区域内找到。这些TEs包括几个与人类炎症和疾病直接相关的TEs，它们与我们研究的受试者的认知/功能诊断、年龄以及炎症和神经退行性变的生物标志物有关。总的来说，这些发现与表观遗传改变可能导致TE转录本失调的观点一致，而TE转录本失调在衰老、认知衰退和AD中起重要作用。
