Abstract
BackgroundRibosomal 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.Methodology/Principal FindingsTo 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.Conclusions/SignificanceIn 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.
Highlights
Regulation of gene expression is achieved through genetic and epigenetic mechanisms
To determine the correlations between Alzheimer’s disease (AD) pathology and methyl-cytosine content in the rDNA promoter, genomic DNA was prepared from post mortem cerebrocortical samples of 23 AD patients, 10 mild cognitive impairment (MCI) patients and 24 age-matched control individuals (Table 1)
Potential polymorphisms removing CpGs were detected in individual rDNA clones, their relative rarity and limited extent further support the notion that bisulfite mapping analysis was not confounded by variations in DNA sequence
Summary
Regulation of gene expression is achieved through genetic and epigenetic mechanisms. While the former are strictly determined by the DNA sequence, the latter are not [1]. Instead, they involve chemical modifications of DNA and/or histones. Cytosine methylation at DNA CpG sites is the principal epigenetic modification of DNA that silences gene expression [2]. Epigenetic regulation may be a part of genetically-determined programs such as X chromosome inactivation, it may mediate the effects of environmental factors [1,2]. The nucleolar rRNA genes (rDNA), transcription of which is critical for ribosomal biogenesis, are regulated by epigenetic silencing including promoter CpG methylation
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