Growth retardation and premature aging phenotypes in mice with disruption of the SNF2-like gene, PASG

Lin Quan Sun, David W. Lee, Quangeng Zhang, Weihong Xiao, Eric Raabe, Alan Keith Meeker, Dengshun Miao, David L. Huso, Robert J. Arceci

Research output: Contribution to journalArticle

Abstract

Imperfect maintenance of genome integrity has been postulated to be an important cause of aging. Here we provide support for this hypothesis by demonstrating that the disruption of PASG (lsh), a SNF2-like factor that facilitates DNA methylation, causes global hypomethylation, developmental growth retardation and a premature aging phenotype. PASG mutant mice display signs of growth retardation and premature aging, including low birth weight, failure to thrive, graying and loss of hair, reduced skin fat deposition, osteoporosis, kyphosis, cachexia, and premature death. Fibroblasts derived from PASG mutant embryos show a replicative senescence phenotype. Both PASG mutant mice and fibroblasts demonstrate a markedly increased expression of senescence-associated tumor suppressor genes, such as p16INK4a, that is independent of promoter methylation, but, instead, is associated with down-regulation of bmi-1, a negative regulator of p16INK4a. These studies show that PASG is essential for properly maintaining DNA methylation and gene expression patterns that are required for normal growth and longevity. PASG mutant mice provide a useful model for the study of aging as well as the mechanisms regulating epigenetic patterning during development and postnatal life.

Original languageEnglish (US)
Pages (from-to)1035-1046
Number of pages12
JournalGenes & development
Volume18
Issue number9
DOIs
StatePublished - May 1 2004

Fingerprint

Premature Aging
DNA Methylation
Phenotype
Growth
Fibroblasts
Genes
Failure to Thrive
Kyphosis
Cachexia
Premature Mortality
Cell Aging
Alopecia
Low Birth Weight Infant
Tumor Suppressor Genes
Epigenomics
Methylation
Osteoporosis
Down-Regulation
Embryonic Structures
Fats

Keywords

  • Aging
  • Genomic instability
  • lsh
  • Methylation
  • PASG
  • Senescence
  • SMARCA6

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Growth retardation and premature aging phenotypes in mice with disruption of the SNF2-like gene, PASG. / Sun, Lin Quan; Lee, David W.; Zhang, Quangeng; Xiao, Weihong; Raabe, Eric; Meeker, Alan Keith; Miao, Dengshun; Huso, David L.; Arceci, Robert J.

In: Genes & development, Vol. 18, No. 9, 01.05.2004, p. 1035-1046.

Research output: Contribution to journalArticle

Sun, Lin Quan ; Lee, David W. ; Zhang, Quangeng ; Xiao, Weihong ; Raabe, Eric ; Meeker, Alan Keith ; Miao, Dengshun ; Huso, David L. ; Arceci, Robert J. / Growth retardation and premature aging phenotypes in mice with disruption of the SNF2-like gene, PASG. In: Genes & development. 2004 ; Vol. 18, No. 9. pp. 1035-1046.
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