Department of Neurology, University Clinic, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Baden-Wuerttemberg, Germany.
Medical Faculty, University of Ulm, 89081, Ulm, Baden-Wuerttemberg, Germany.
Cell Mol Life Sci. 2023 Apr 24;80(5):131. doi: 10.1007/s00018-023-04769-w.
Amyotrophic Lateral Sclerosis (ALS) is a complex and incurable neurodegenerative disorder in which genetic and epigenetic factors contribute to the pathogenesis of all forms of ALS. The interplay of genetic predisposition and environmental footprints generates epigenetic signatures in the cells of affected tissues, which then alter transcriptional programs. Epigenetic modifications that arise from genetic predisposition and systemic environmental footprints should in theory be detectable not only in affected CNS tissue but also in the periphery. Here, we identify an ALS-associated epigenetic signature ('epiChromALS') by chromatin accessibility analysis of blood cells of ALS patients. In contrast to the blood transcriptome signature, epiChromALS includes also genes that are not expressed in blood cells; it is enriched in CNS neuronal pathways and it is present in the ALS motor cortex. By combining simultaneous ATAC-seq and RNA-seq with single-cell sequencing in PBMCs and motor cortex from ALS patients, we demonstrate that epigenetic changes associated with the neurodegenerative disease can be found in the periphery, thus strongly suggesting a mechanistic link between the epigenetic regulation and disease pathogenesis.
肌萎缩侧索硬化症（ALS）是一种复杂且无法治愈的神经退行性疾病，其中遗传和表观遗传因素促成了所有形式 ALS 的发病机制。遗传易感性和环境印记的相互作用在受影响组织的细胞中产生表观遗传特征，从而改变转录程序。遗传易感性和全身性环境印记产生的表观遗传修饰不仅应该在受影响的中枢神经系统组织中，而且应该在外周组织中被检测到。在这里，我们通过对 ALS 患者的血细胞进行染色质可及性分析来鉴定与 ALS 相关的表观遗传特征（“epiChromALS”）。与血液转录组特征相比，epiChromALS 还包含不在血细胞中表达的基因；它富集在中枢神经系统神经元途径中，存在于 ALS 运动皮层中。通过在 ALS 患者的 PBMC 和运动皮层中同时进行 ATAC-seq 和 RNA-seq 与单细胞测序，我们证明与神经退行性疾病相关的表观遗传变化可以在外周组织中找到，因此强烈表明表观遗传调控和疾病发病机制之间存在机制联系。
