C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD

Details

• Alternative Title:
  Acta Neuropathol
• Personal Author:
  Liu, Elaine Y. ; Russ, Jenny ; Wu, Kathryn ; Neal, Donald ; Suh, Eunran ; McNally, Anna G. ; Irwin, David J. ; Van Deerlin, Vivianna M. ; Lee, Edward B.
• Description:
  Hexanucleotide repeat expansions of C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal degeneration. The mutation is associated with reduced C9orf72 expression and the accumulation of potentially toxic RNA and protein aggregates. CpG methylation is known to protect the genome against unstable DNA elements and to stably silence inappropriate gene expression. Using bisulfite cloning and restriction enzyme-based methylation assays on DNA from human brain and peripheral blood, we observed CpG hypermethylation involving the C9orf72 promoter in cis to the repeat expansion mutation in approximately one-third of C9orf72 repeat expansion mutation carriers. Promoter hypermethylation of mutant C9orf72 was associated with transcriptional silencing of C9orf72 in patient-derived lymphoblast cell lines, resulting in reduced accumulation of intronic C9orf72 RNA and reduced numbers of RNA foci. Furthermore, demethylation of mutant C9orf72 with 5-aza-deoxycytidine resulted in increased vulnerability of mutant cells to oxidative and autophagic stress. Promoter hypermethylation of repeat expansion carriers was also associated with reduced accumulation of RNA foci and dipeptide repeat protein aggregates in human brains. These results indicate that C9orf72 promoter hypermethylation prevents downstream molecular aberrations associated with the hexanucleotide repeat expansion, suggesting that epigenetic silencing of the mutant C9orf72 allele may represent a protective counter-regulatory response to hexanucleotide repeat expansion.
• Subjects:
  Aged Aged, 80 And Over Amyotrophic Lateral Sclerosis Analysis Of Variance C9orf72 Protein Cell Line, Transformed CpG Islands DNA Methylation DNA Mutational Analysis DNA Repeat Expansion Female Frontotemporal Dementia Gene Expression Regulation Humans Male Middle Aged Mutation Promoter Regions, Genetic Proteins RNA, Messenger

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• Keywords:
  Amyotrophic Lateral Sclerosis Dementia Epigenetics Frontotemporal Lobar Degeneration Motor Neuron Disease Neurodegeneration
• Source:
  Acta Neuropathol. 2014; 128(4):525-541
• Pubmed ID:
  24806409
• Pubmed Central ID:
  PMC4161616
• Document Type:
  Journal Article
• Funding:
  P01 AG032953/AG/NIA NIH HHSUnited States/ ; T32AG00255/AG/NIA NIH HHSUnited States/ ; P01 AG017586/AG/NIA NIH HHSUnited States/ ; T32 AG000255/AG/NIA NIH HHSUnited States/ ; K08 AG039510/AG/NIA NIH HHSUnited States/ ; P01AG017586/AG/NIA NIH HHSUnited States/ ; P30AG10125/AG/NIA NIH HHSUnited States/ ; P01AG032953/AG/NIA NIH HHSUnited States/ ; ND14442/ND/ONDIEH CDC HHSUnited States/ ; K08AG039510/AG/NIA NIH HHSUnited States/ ; P30 AG010124/AG/NIA NIH HHSUnited States/ ; ND10966/ND/ONDIEH CDC HHSUnited States/ ; ND16183/ND/ONDIEH CDC HHSUnited States/ ; K23 NS088341/NS/NINDS NIH HHSUnited States/ ; ND11836/ND/ONDIEH CDC HHSUnited States/
• Volume:
  128
• Issue:
  4
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:7c2a44fe6fe4dc5bc829797b01cd79455100c8cb140e83ec79a5c8413c83acd6
• Download URL:
  https://stacks.cdc.gov/view/cdc/30113/cdc_30113_DS1.pdf
• File Type:
  [PDF - 1.36 MB ]