We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive “multi-omic” analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease. Our results strongly implicate SERPINA1 in both C9orf72 repeat expansion carriers and non-carriers, where expression levels are greatly increased in both patient groups across the frontal cortex and cerebellum. SERPINA1 expression is particularly pronounced in C9orf72 repeat expansion carriers for both brain regions, where SERPINA1 levels are strictly down regulated across most human tissues, including the brain, except liver and blood, and are not measurable in E18 mouse brain. The altered biological networks we identified contain critical molecular players known to contribute to ALS pathology, which also interact with SERPINA1. Our comprehensive combined methylation and transcription study identifies new genes and highlights that direct genetic and epigenetic changes contribute to c9ALS and sALS pathogenesis.

我们以前发现C9orf72相关（c9ALS）和偶发性肌萎缩性侧索硬化（sALS）脑转录组包含数千个缺陷，其中一些可能是ALS发病机理的关键因素。现在，我们已经生成了互补的甲基化组数据，并将这两个数据集结合起来进行了全面的“多组学”分析，以阐明引发ALS中RNA失调的分子机制。我们发现，c9ALS和sALS患者通常具有截然不同但重叠的甲基化组特征，并且受c9ALS和sALS影响的基因和途径具有相似的生物学功能，这表明该病的病理生物学性质是保守的。我们的结果强烈暗示了SERPINA1在两个C9orf72中重复扩增载体和非载体，其中在额叶皮层和小脑的两个患者组中的表达水平都大大提高。SERPINA1表达在两个大脑区域的C9orf72重复扩增载体中特别明显，在该区域中，SERPINA1的水平在包括肝脏和血液在内的大多数人体组织中都被严格下调，而在E18小鼠大脑中无法测量。我们鉴定出的改变后的生物网络包含已知有助于ALS病理学的重要分子，这些分子也与SERPINA1相互作用。。我们全面的甲基化和转录结合研究确定了新基因，并着重指出直接的遗传和表观遗传学变化有助于c9ALS和sALS的发病机理。