Cited by 180Amyotrophic Lateral Sclerosis ResearchEpigenetics and DNA MethylationGenetic Neurodegenerative Diseases

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

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Liu, Elaine Y., Russ, Jenny, Wu, Kathryn, Neal, Donald, Suh, Eunran, McNally, Anna G., Irwin, David J., Van Deerlin, Vivianna M., Lee, Edward B.·2014·Acta Neuropathologica

DOI 10.1007/s00401-014-1286-yPMC PMC4161616

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Abstract

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.

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Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,312
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Rinaldi, C., & Wood, M. J. A. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.148 · Cited by 788
C9orf72-mediated ALS and FTD: multiple pathways to disease
Balendra, R., & Isaacs, A. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0047-2 · Cited by 715
Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons
Shi, Y., Lin, S., Staats, K. A., Li, Y., Chang, W.-H., Hung, S.-T., Hendricks, E., Linares, G. R., Wang, Y., Son, E. Y., et al. (2018) · Nature Medicine · doi:10.1038/nm.4490 · Cited by 566
Gain of toxicity from ALS/FTD-linked repeat expansions in C9ORF72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs
Jiang, J., Zhu, Q., Gendron, T. F., Saberi, S., McAlonis-Downes, M., Seelman, A., Stauffer, J. E., Jafar-nejad, P., Drenner, K., Schulte, D., et al. (2016) · Neuron · doi:10.1016/j.neuron.2016.04.006 · Cited by 536

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Authors: Liu, E. Y., Russ, J., Wu, K., Neal, D., Suh, E., McNally, A. G., Irwin, D. J., Van Deerlin, V. M., & Lee, E. B.
Affiliations: University of Pennsylvania (US)
Corresponding author: Lee, Edward B.
ORCID: Russ, Jenny
Wu, Kathryn
Suh, Eunran
McNally, Anna G.
Irwin, David J.
Lee, Edward B.
Venue: Acta Neuropathologica
Publisher: Springer Science and Business Media LLC
Published: 2014-05-08
Volume: 128
Issue: 4
Pages: 525-541
ISSN: 0001-6322 (ISSN-L)
1432-0533
DOI: 10.1007/s00401-014-1286-y
PMC: PMC4161616
OpenAlex: W1982725145
Cited by: 180
References: 68
Citations by year: 2026: 4 · 2025: 10 · 2024: 9 · 2023: 7 · 2022: 6 · 2021: 17 · 2020: 15 · 2019: 17 · 2018: 19 · 2017: 20 · 2016: 19 · 2015: 30 · 2014: 7
FWCI: 16.52
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Acta Neuropathologica (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Centers for Disease Control and Prevention (ND14442, ND11836, ND16183, ND10966)
National Institute on Aging (P30AG10125, T32 AG 00255, P30AG010124, P01AG017586, K08AG039510, P01AG032953, T32AG000255)
National Institute of Neurological Disorders and Stroke (K23NS088341)
Topics: Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords: C9orf72, hexanucleotide repeat expansion, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, CpG hypermethylation, promoter hypermethylation, epigenetic silencing, RNA foci, oxidative stress
MeSH terms: C9orf72 Protein, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Analysis of Variance, Cell Line, Transformed, DNA Mutational Analysis, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Mutation, Promoter Regions, Genetic, Proteins, RNA, Messenger, CpG Islands, DNA Methylation, DNA Repeat Expansion, Frontotemporal Dementia

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

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