We used an RNAi library of chromatin factors to screen for lifespan extension in C. elegans. This identified two factors
mes-2 and
jmjd-3.2, both affecting methylation at lysine 27 of histone 3 (H3K27). Intriguingly,
mes-2 encodes a histone methyltransferase while
jmjd-3.2 was identified as a demethylase, thus these two proteins display opposing enzymatic activities yet knockdown of either results in lifespan extension. Heterozygous mutation of another
jmjd-3.2 family member,
utx-1, has also been reported to prolong lifespan by increasing H3K27 methylation on
daf-2 (Jin et al, 2011). Homozygous
utx-1 mutants display severe developmental defects, however the role of
utx-1 in development is independent of its enzymatic activity, as demethylase dead (DD)
utx-1 still rescues the developmental phenotypes (Vandamme et al, 2012). In contrast, we show that
utx-1 enzymatic activity is required for the lifespan increase in
utx-1 mutants as the DD mutant fails to rescue the lifespan extension phenotype. Furthermore, overexpression of wild-type
utx-1, but not DD
utx-1, causes a dramatic increase in lifespan in both
utx-1 mutant and wild-type backgrounds. Analysis of the tissue specificity of this effect has revealed that intestinal and neuronal expression, but not muscle or hypodermal expression, results in lifespan extension.Overexpression of either
mes-2 or
jmjd-3.2 also increases lifespan, although in the case of
jmjd-3.2 this is not dependent on its enzymatic function, suggesting a different mode of action from
utx-1.Overall, these results suggest that disturbing the balance of H3K27 methylation has important consequences for lifespan regulation in C. elegans. We are currently identifying critical targets of H3K27 methylation modifiers involved in this lifespan regulation. Jin C., Li J., Green C.D., Yu X., Tang X., Han D., Xian B., Wang D., Huang X., Cao X., Yan Z., Hou L., Liu J., Shukeir N., Khaitovich P., Chen C.D., Zhang H., Jenuwein T., Han J-D.J. (2011) Cell Metabolism 14(2).Vandamme J., Lettier G., Sidoli S., Schiavi E.D., Jensen O.N., Salcini A.E. (2012) PLOS Genetics 8(5). .