title: Epigenetic silencing of nucleolar rRNA genes in Alzheimer's disease.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurological Surgery and Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky United States of America.
authors.forename: Maciej
authors.initials: M
authors.lastname: Pietrzak
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Rempala
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nelson
authors.forename: Jing-Juan
authors.initials: JJ
authors.lastname: Zheng
authors.forename: Michal
authors.initials: M
authors.lastname: Hetman
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D001483:Base Sequence; D002466:Cell Nucleolus / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D004275:DNA, Ribosomal / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D012335:RNA, Ribosomal / Q000235:genetics*
chemical_list: D004275:DNA, Ribosomal; D012335:RNA, Ribosomal; D003596:Cytosine