Hypomorphic Mouse Mutant of PASG, an SNF2L factor, that leads to growth retardation and premature aging that is associated with replicative senescence, genetic instability, decreased stem cell expansi

Researchers at JHU have shown that PASG (Proliferation Associated SNF2-Like gene, also termed lsh or SMARCA6) is essential for properly maintaining DNA methylation and gene expression patterns which are required for normal growth and longevity. PASG, a facilitator of DNA methylation, causes global DNA hypomethylation, developmental growth retardation and a premature aging phenotype. This invention relates to the identification of a gene termed PASG and the generation of a hypomorphic mutant mouse by homologous recombination. The mutant mouse was generated by a deletion that removes the conserved domains II, III and IV of the PASG protein. This mouse displays 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. Description (Set) Proposed Use (Set) 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 as well as cancer pathogenesis and treatment. These animals may provide models for elucidating mechanisms of adipose formation and bone growth and skeletal defects and can perhaps be exploited for the identification of molecular pathways regulating these important biological processes as well as defining new therapeutic targets that regulate cell growth, replicative senescence, premature aging, genetic instability, gene regulation, cancer pathogenesis and treatment, adipose tissue development and homeostasis as well as bone formation.

Inventor(s): Arceci, Robert

Type of Offer: Licensing

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