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.
Sun
Lin-Quan
LQ
Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Lee
David W
DW
Zhang
Quangeng
Q
Xiao
Weihong
W
Raabe
Eric H
EH
Meeker
Alan
A
Miao
Dengshun
D
Huso
David L
DL
Arceci
Robert J
RJ
D019588:Aging, Premature / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004265:DNA Helicases / Q000172:deficiency* / Q000235:genetics*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D015870:Gene Expression; D018390:Gene Targeting; D016147:Genes, Tumor Suppressor; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*
C489421:Bmi1 protein, mouse; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; D004247:DNA; D063150:Polycomb Repressive Complex 1; C513194:Smarca4 protein, mouse; D004265:DNA Helicases; C487055:Hells protein, mouse