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

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 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.

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

“…Some genetic models with shortened lifespan showed accelerated aging or increased cancer incidence with subsequent lifespan decreases of 25-50 % (Rudolph et al 1999;Keyes et al 2005). We observed signs of accelerated aging including reduced body weight, alopecia, and spine curvature in our model, but did not examine other factors such as bone density or cellular senescence (de Boer et al 2002;Sun et al 2004). Cancer incidence was similar to WT mice.…”

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

“…Collectively, these abnormalities (weight loss, hair loss, osteoporosis, lordokyphosis, muscle atrophy, and reduced life span) are indicative of premature aging, and are common clinical features in human and rodent aging. 2,3,[27][28][29][30][31][32] Loss of HtrA2 causes cardiac aging, increased extramedullary hematopoiesis and splenomegaly. Gross anatomical examination of the heart from 15-month-old rescued mnd2 mice showed clear enlargement of the heart as compared with control animals (Figure 3a), with an increase in the left ventricular chamber size.…”

“…2,3,[27][28][29][30][31][32] Pathological heart enlargement, particularly left ventricular hypertrophy, is a physiological change associated with cardiac aging and a major risk factor affecting life span. Adult rescued mnd2 mice exhibit clear features of cardiac aging including left ventricular hypertrophy, decreased glucose metabolism, increased mtDNA deletions and increased autophagosome activity.…”

Epigenetics and cancer

“…Finally, nucleosome remodeling can affect DNA methylation, as evident from genetic studies in Arabidopsis thaliana, where mutation of the SNF2-like gene DDM1 causes a dramatic decrease in the level of genomic cytosine methylation (Jeddeloh et al 1999). In the mouse, disruption of the Lsh locus encoding the SNF2-like helicase PASG results in genomic demethylation (Dennis et al 2001;Sun et al 2004), demonstrating concerted functionality between nucleosome remodeling and DNA methylation. Lsh deficiency also affects histone methylation patterns at pericentromeric heterochromatin, resulting in the accumulation of methylated Lys 4 of histone H3 and pointing to cross-talk between epigenetic layers of regulation (Yan et al 2003).…”

“…Interestingly, abrogation of the lsh locus results in a dramatic induction of the cyclin-dependent kinase inhibitor p16 Ink4a (Sun et al 2004). This effect is independent of p16 Ink4a promoter methylation but could in part be explained by reduced levels of the known p16 Ink4a regulator Polycomb protein Bmi1 in lsh knockouts (Sun et al 2004).…”