Genome dynamics and transcriptional deregulation in aging

R. Busuttil, R. Bahar, Jan Vijg

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Genome instability has been implicated as a major cause of both cancer and aging. Using a lacZ-plasmid transgenic mouse model we have shown that mutations accumulate with age in a tissue-specific manner. Genome rearrangements, including translocations and large deletions, are a major component of the mutation spectrum in some tissues at old age such as heart. Such large mutations were also induced by hydrogen peroxide (H2O2) in lacZ-plasmid mouse embryonic fibroblasts (MEFs) and demonstrated to be replication-independent. This was in contrast to ultraviolet light-induced point mutations, which were much more abundant in proliferating than in quiescent MEFs. To test if large rearrangements could adversely affect patterns of gene expression we PCR-amplified global mRNA content of single MEFs treated with H2O2. Such treatment resulted in a significant increase in cell-to-cell variation in gene expression, which was found to parallel the induction and persistence of genome rearrangement mutations at the lacZ reporter locus. Increased transcriptional noise was also found among single cardiomyocytes from old mice as compared with similar cells from young mice. While these results do not directly indicate a cause and effect relationship between genome rearrangement mutations and transcriptional deregulation, they do underscore the stochastic nature of genotoxic effects on cells and tissues and could provide a mechanism for age-related cellular degeneration in postmitotic tissue, such as heart or brain.

Original languageEnglish (US)
Pages (from-to)1341-1347
Number of pages7
JournalNeuroscience
Volume145
Issue number4
DOIs
StatePublished - Apr 14 2007
Externally publishedYes

Fingerprint

Genome
Mutation
Fibroblasts
Plasmids
Gene Expression
Genomic Instability
Ultraviolet Rays
Point Mutation
Cardiac Myocytes
Hydrogen Peroxide
Transgenic Mice
Noise
Polymerase Chain Reaction
Messenger RNA
Brain
Neoplasms

Keywords

  • cell-to-cell variation
  • gene regulation
  • genome instability
  • single cell
  • somatic mutations

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Genome dynamics and transcriptional deregulation in aging. / Busuttil, R.; Bahar, R.; Vijg, Jan.

In: Neuroscience, Vol. 145, No. 4, 14.04.2007, p. 1341-1347.

Research output: Contribution to journalArticle

Busuttil, R. ; Bahar, R. ; Vijg, Jan. / Genome dynamics and transcriptional deregulation in aging. In: Neuroscience. 2007 ; Vol. 145, No. 4. pp. 1341-1347.
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