X-Message-Number: 24310
Date: Tue, 29 Jun 2004 19:00:26 -0700 (PDT)
From: Doug Skrecky <>
Subject: premature aging phenotypes in mice

Genes Dev. 2004 May 1;18(9):1035-46. Epub 2004 Apr 22.
Growth retardation and premature aging phenotypes in mice with disruption
of the SNF2-like gene, PASG.
  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 p16(INK4a), that is independent of promoter methylation, but,
instead, is associated with down-regulation of bmi-1, a negative regulator
of p16(INK4a). 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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