Epigenetic silencing of nucleolar rRNA genes in Alzheimer's disease

• Published in: PloS one Vol. 6; no. 7; p. e22585
• Main Authors: Pietrzak, Maciej, Rempala, Grzegorz, Nelson, Peter T, Zheng, Jing-Juan, Hetman, Michal
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22-07-2011; Public Library of Science (PLoS)
• Subjects: Advertising executives; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer's disease; Analysis; Apoptosis; Base Sequence; Biology; Biosynthesis; Bisulfite; Brain; Brain research; Cell Nucleolus - genetics; Chromatin; Chromosomes; Cloning; Cognitive ability; Colorectal cancer; Cortex (parietal); CpG islands; CpG Islands - genetics; Cytosine; Cytosine - metabolism; Dementia disorders; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - genetics; DNA, Ribosomal - genetics; Epigenesis, Genetic - genetics; Epigenetic inheritance; Epigenetics; Female; Gene expression; Gene mapping; Gene Silencing; Genes; Genetic aspects; Genetic engineering; Humans; Male; Medicine; Methylation; Molecular Sequence Data; Neurodegenerative diseases; Nucleoli; Pathogenesis; Pathology; Polymerase chain reaction; Promoter Regions, Genetic - genetics; Pyrimidines; RNA; RNA, Ribosomal - genetics; rRNA; Senescence; Singers; Sperm; Spinal cord injuries; Sulfites; Surgery; Transcription; Transcription (Genetics); United States > US; Kentucky
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0022585

Ribosomal deficits are documented in mild cognitive impairment (MCI), which often represents an early stage Alzheimer's disease (AD), as well as in advanced AD. The nucleolar rRNA genes (rDNA), transcription of which is critical for ribosomal biogenesis, are regulated by epigenetic silencing including promoter CpG methylation.
To assess whether CpG methylation of the rDNA promoter was dysregulated across the AD spectrum, we analyzed brain samples from 10 MCI-, 23 AD-, and, 24 age-matched control individuals using bisulfite mapping. The rDNA promoter became hypermethylated in cerebro-cortical samples from MCI and AD groups. In parietal cortex, the rDNA promoter was hypermethylated more in MCI than in advanced AD. The cytosine methylation of total genomic DNA was similar in AD, MCI, and control samples. Consistent with a notion that hypermethylation-mediated silencing of the nucleolar chromatin stabilizes rDNA loci, preventing their senescence-associated loss, genomic rDNA content was elevated in cerebrocortical samples from MCI and AD groups.
In conclusion, rDNA hypermethylation could be a new epigenetic marker of AD. Moreover, silencing of nucleolar chromatin may occur during early stages of AD pathology and play a role in AD-related ribosomal deficits and, ultimately, dementia.