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

  1. Lin-Quan Sun1,
  2. David W. Lee1,
  3. Quangeng Zhang1,
  4. Weihong Xiao3,
  5. Eric H. Raabe1,
  6. Alan Meeker2,
  7. Dengshun Miao4,
  8. David L. Huso5, and
  9. Robert J. Arceci1,6
  1. 1Division of Pediatric Oncology, and 2Division of Experimental Therapeutics, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA; 3Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA; 4Calcium Research Laboratory, Department of Medicine, McGill University, Royal Victoria Hospital, Montreal, Quebec, H3A 1A1, Canada; 5Department of Comparative Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

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.

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Footnotes

  • Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1176104.

  • ↵6 Corresponding author. E-MAIL arcecro{at}jhmi.edu; FAX (410) 502-7223.

    • Accepted March 22, 2004.
    • Received December 8, 2003.
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This Article

  1. Published in Advance April 22, 2004, doi: 10.1101/gad.1176104 Genes & Dev. 18: 1035-1046 Cold Spring Harbor Laboratory Press

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