Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging

Genes Dev. 2014 Feb 15;28(4):396-408. doi: 10.1101/gad.233221.113.


All eukaryotic cells divide a finite number of times, although the mechanistic basis of this replicative aging remains unclear. Replicative aging is accompanied by a reduction in histone protein levels, and this is a cause of aging in budding yeast. Here we show that nucleosome occupancy decreased by 50% across the whole genome during replicative aging using spike-in controlled micrococcal nuclease digestion followed by sequencing. Furthermore, nucleosomes became less well positioned or moved to sequences predicted to better accommodate histone octamers. The loss of histones during aging led to transcriptional induction of all yeast genes. Genes that are normally repressed by promoter nucleosomes were most induced, accompanied by preferential nucleosome loss from their promoters. We also found elevated levels of DNA strand breaks, mitochondrial DNA transfer to the nuclear genome, large-scale chromosomal alterations, translocations, and retrotransposition during aging.

Keywords: DNA rearrangement; gene expression; histone occupancy; replicative aging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / genetics*
  • Chromosome Aberrations
  • DNA Breaks
  • DNA, Mitochondrial / genetics
  • Gene Expression Regulation, Fungal
  • Genome, Fungal / genetics*
  • Genomic Instability / genetics*
  • Histones / metabolism
  • Nucleosomes / physiology*
  • Promoter Regions, Genetic / genetics
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism*
  • TATA Box / genetics
  • Up-Regulation*


  • DNA, Mitochondrial
  • Histones
  • Nucleosomes