Physiological roles of the DNA demethylation-associated proteins Gadd45a and Ing1
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Abstract
Active DNA demethylation is essential for regulating epigenetic gene activation. The Growth arrest- and DNA damage-inducible protein 45 alpha (Gadd45a) is involved in DNA demethylation and is targeted to chromatin by the H3K4me3 reader Inhibitor of growth protein 1 (Ing1). The physiological roles of Gadd45a- and Ing1 mediated DNA demethylation are largely unknown. Using knockout mice, I demonstrate that loss of Gadd45a and Ing1 synergistically leads to premature aging. Mice deficient of Gadd45a and Ing1 suffer from shortened lifespan, failure to thrive, kyphosis, weight reduction, ovarian atrophy, and female infertility. Hypotrophy of adipose tissue in Gadd45a- and Ing1-deficient mice is correlated to browning of white adipose tissue and organism-wide elevated catabolism. Adipose tissue hypotrophy is recapitulated in vitro by a failure of Gadd45a- and Ing1 deficient cells to differentiate along the adipogenic lineage – a phenotype that is correlated to local DNA hypermethylation of differentiation-associated genes. These results uncover a role for Gadd45a and Ing1 in aging and highlight DNA demethylation as a potential determinant of lifespan regulation.