Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans

Abstract

Genes of the Sir2 family are known to influence longevity in yeast, in the worm Caenorhabditis elegans and in other organisms through an effect on histone deacetylation. This raises the question of whether other histone modifications also influence longevity. Greer et al. show that histone methylation regulates lifespan determination in C. elegans. Deficiencies in components of a conserved chromatin protein complex known as the ASH-2 complex, which trimethylates histone H3 at lysine 4 (H3K4), all extend worm lifespan. Conversely, the H3K4 demethylase RBR-2 is required for normal lifespan, consistent with the idea that an excess of H3K4 trimethylation shortens lifespan. This increase in longevity requires the presence of an intact adult germline and the continuous production of mature eggs, which suggests that the lifespan of the soma is regulated by an H3K4 methyltransferase/demethylase complex in the germline. It is shown here that the methylation of histone proteins regulates lifespan in Caenorhabditis elegans. Deficiencies in members of the ASH-2 complex, which trimethylates histone H3 at lysine 4 (H3K4), extend worm lifespan. Meanwhile, the H3K4 demethylase RBR-2 is required for normal lifespan. These findings are consistent with the idea that an excess of H3K4 trimethylation reduces longevity. The extension of lifespan caused by ASH-2 deficiency requires an intact adult germline and the continuous production of mature eggs. The plasticity of ageing suggests that longevity may be controlled epigenetically by specific alterations in chromatin state. The link between chromatin and ageing has mostly focused on histone deacetylation by the Sir2 family1,2, but less is known about the role of other histone modifications in longevity. Histone methylation has a crucial role in development and in maintaining stem cell pluripotency in mammals3. Regulators of histone methylation have been associated with ageing in worms4,5,6,7 and flies8, but characterization of their role and mechanism of action has been limited. Here we identify the ASH-2 trithorax complex9, which trimethylates histone H3 at lysine 4 (H3K4), as a regulator of lifespan in Caenorhabditis elegans in a directed RNA interference (RNAi) screen in fertile worms. Deficiencies in members of the ASH-2 complex—ASH-2 itself, WDR-5 and the H3K4 methyltransferase SET-2—extend worm lifespan. Conversely, the H3K4 demethylase RBR-2 is required for normal lifespan, consistent with the idea that an excess of H3K4 trimethylation—a mark associated with active chromatin—is detrimental for longevity. Lifespan extension induced by ASH-2 complex deficiency requires the presence of an intact adult germline and the continuous production of mature eggs. ASH-2 and RBR-2 act in the germline, at least in part, to regulate lifespan and to control a set of genes involved in lifespan determination. These results indicate that the longevity of the soma is regulated by an H3K4 methyltransferase/demethylase complex acting in the C. elegans germline.