School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands.
School for Mental Health and Neuroscience (MHeNs), Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Computational Biology Group, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg; Biomedical Data Science Group, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg.
Neurobiol Aging. 2021 Jun;102:178-187. doi: 10.1016/j.neurobiolaging.2021.02.001. Epub 2021 Feb 7.
Sphingolipids (SLs) are bioactive lipids involved in various important physiological functions. The SL pathway has been shown to be affected in several brain-related disorders, including Alzheimer's disease (AD). Recent evidence suggests that epigenetic dysregulation plays an important role in the pathogenesis of AD as well. Here, we use an integrative approach to better understand the relationship between epigenetic and transcriptomic processes in regulating SL function in the middle temporal gyrus of AD patients. Transcriptomic analysis of 252 SL-related genes, selected based on GO term annotations, from 46 AD patients and 32 healthy age-matched controls, revealed 103 differentially expressed SL-related genes in AD patients. Additionally, methylomic analysis of the same subjects revealed parallel hydroxymethylation changes in PTGIS, GBA, and ITGB2 in AD. Subsequent gene regulatory network-based analysis identified 3 candidate genes, that is, SELPLG, SPHK1 and CAV1 whose alteration holds the potential to revert the gene expression program from a diseased towards a healthy state. Together, this epigenomic and transcriptomic approach highlights the importance of SL-related genes in AD, and may provide novel biomarkers and therapeutic alternatives to traditionally investigated biological pathways in AD.
鞘脂（SLs）是参与多种重要生理功能的生物活性脂质。SL 途径已被证明在几种与大脑相关的疾病中受到影响，包括阿尔茨海默病（AD）。最近的证据表明，表观遗传失调在 AD 的发病机制中也起着重要作用。在这里，我们采用综合方法来更好地了解 AD 患者中中颞叶 SL 功能调节的表观遗传和转录组过程之间的关系。对 46 名 AD 患者和 32 名年龄匹配的健康对照者的 252 个 SL 相关基因进行转录组分析，这些基因是根据 GO 术语注释选择的，结果显示 AD 患者中有 103 个 SL 相关基因表达差异。此外，对同一受试者的甲基化组分析显示 AD 中 PTGIS、GBA 和 ITGB2 的羟甲基化变化平行。随后基于基因调控网络的分析确定了 3 个候选基因，即 SELPLG、SPHK1 和 CAV1，其改变有可能使基因表达程序从疾病状态恢复到健康状态。总之，这种表观基因组学和转录组学方法强调了 SL 相关基因在 AD 中的重要性，并可能为 AD 中传统研究的生物学途径提供新的生物标志物和治疗替代方案。
