title: Characterization of DNA hypermethylation in the cerebellum of c9FTD/ALS patients.
abstract: A significant number of patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two diseases commonly seen in comorbidity, carry an expanded noncoding hexanucleotide repeat in the C9orf72 gene, a condition collectively referred to as c9FTD/ALS. Repeat expansions, also present in other neurodegenerative diseases, have been shown to alter epigenetic mechanisms and consequently lead to decreased gene expression, while also leading to toxic RNA gain-of-function. As expression of multiple C9orf72 transcript variants is known to be reduced in c9FTD/ALS cases, our group and others have sought to uncover the mechanisms causing this reduction. We recently demonstrated that histones H3 and H4 undergo trimethylation at lysines 9 (H3K9), 27 (H3K27), 79 (H3K79), and 20 (H4K20) in all pathogenic repeat carrier brain samples, confirming the role of altered histone methylation in disease. It was also reported that about 40% of c9ALS cases show hypermethylation of the CpG island located at the 5' end of the repeat expansion in blood, frontal cortex, and spinal cord. To determine whether the same CpG island is hypermethylated in the cerebella of cases in whom aberrant histone methylation has been identified, we bisulfite-modified the extracted DNA and PCR-amplified 26 CpG sites within the C9orf72 promoter region. Among the ten c9FTD/ALS (4 c9ALS, 6 c9FTD), nine FTD/ALS, and eight disease control samples evaluated, only one c9FTD sample was found to be hypermethylated within the C9orf72 promoter region. This study is the first to report cerebellar hypermethylation in c9FTD/ALS, and the first to identify a c9FTD patient with aberrant DNA methylation. Future studies will need to evaluate hypermethylation of the C9orf72 promoter in a larger cohort of c9FTD patients, and to assess whether DNA methylation variation across brain regions reflects disease phenotype.
authors: Department of Research, Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address: belzil.veronique@mayo.edu.
authors: Veronique V
authors: VV
authors: Belzil
authors: Department of Research, Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address: bauer.peter@mayo.edu.
authors: Peter O
authors: PO
authors: Bauer
authors: Department of Research, Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address: gendron.tania@mayo.edu.
authors: Tania F
authors: TF
authors: Gendron
authors: Department of Research, Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address: murray.melissa@mayo.edu.
authors: Melissa E
authors: ME
authors: Murray
authors: Department of Research, Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address: dickson.dennis@mayo.edu.
authors: Dennis
authors: D
authors: Dickson
authors: Department of Research, Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address: petrucelli.leonard@mayo.edu.
authors: Leonard
authors: L
authors: Petrucelli
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000073885:C9orf72 Protein; D002531:Cerebellum / Q000378:metabolism*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics*; D006657:Histones / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D006657:Histones; D011506:Proteins
keywords: Amyotrophic lateral sclerosis; C9orf72; DNA methylation; Epigenetics; Frontotemporal dementia; Repeat expansion