Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease.
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.
['Ebbert|Mark T W|MTW|', 'Ross|Christian A|CA|', 'Pregent|Luc J|LJ|', 'Lank|Rebecca J|RJ|', 'Zhang|Cheng|C|', 'Katzman|Rebecca B|RB|', 'Jansen-West|Karen|K|', 'Song|Yuping|Y|', 'da Rocha|Edroaldo Lummertz|EL|', 'Palmucci|Carla|C|', 'Desaro|Pamela|P|', 'Robertson|Amelia E|AE|', 'Caputo|Ana M|AM|', 'Dickson|Dennis W|DW|', 'Boylan|Kevin B|KB|', 'Rademakers|Rosa|R|', 'Ordog|Tamas|T|', 'Li|Hu|H|', 'Belzil|Veronique V|VV|']
D000690:Amyotrophic Lateral Sclerosis D000073885:C9orf72 Protein D002531:Cerebellum D019175:DNA Methylation D042622:DNA Repeat Expansion D005091:Exons D005625:Frontal Lobe D006801:Humans D000515:alpha 1-Antitrypsin
DNA methylation SERPINA1 Amyotrophic lateral sclerosis C9orf72 Epigenetic modification Transcriptome regulation