Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease
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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.
KeywordsAmyotrophic lateral sclerosis C9orf72 DNA methylation Epigenetic modification SERPINA1 Transcriptome regulation
We are extremely grateful to all individuals who agreed to donate their brains to research. This study was supported by the National Institutes of Health/National Institute on Aging [AG16574-17 J PILOT (V.V.B.)]; National Institutes of Health/National Institute of Neurological Disorders and Stroke [R21NS074121 (K.B.B.), P01NS084974 (D.W.D., K.B.B., and R.R.]; Mayo Clinic Center for Individualized Medicine (V.V.B., K.B.B., and H.L.); ALS Association (K.B.B.), Donors Cure Foundation (H.L.), and the Robert Packard Center for ALS Research at Johns Hopkins. V.V.B. is recipient of the Career Transition Award from ALS Canada and Brain Canada, the Milton Safenowitz Post-Doctoral Fellowship from the Amyotrophic Lateral Sclerosis Association, the Post-Doctoral Fellowship from the Canadian Institutes of Health Research, the Career Development Award for Young Investigators in Neurosciences from the Siragusa Foundation, and the Research Fellowship from the Robert and Clarice Smith & Abigail Van Buren Alzheimer’s Disease Research Foundation. M.T.W.E received the PhRMA Foundation Research Starter grant.
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Conflict of interest
The authors declare that they have no conflict of interest.
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