3 years ago

Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72 -associated and sporadic ALS, and implicates SERPINA1 in disease

Hu Li, Tamas Ordog, Luc J. Pregent, Pamela Desaro, Mark T. W. Ebbert, Amelia E. Robertson, Cheng Zhang, Dennis W. Dickson, Carla Palmucci, Yuping Song, Rebecca B. Katzman, Kevin B. Boylan, Veronique V. Belzil, Rosa Rademakers, Edroaldo Lummertz da Rocha, Karen Jansen-West, Rebecca J. Lank, Ana M. Caputo, Christian A. Ross

Abstract

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.

Publisher URL: https://link.springer.com/article/10.1007/s00401-017-1760-4

DOI: 10.1007/s00401-017-1760-4

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