Histone methylation makes its mark on longevity

Abstract

How long organisms live is not entirely written in their genes. Recent findings reveal that epigenetic factors that regulate histone methylation, a type of chromatin modification, can affect lifespan. The reversible nature of chromatin modifications suggests that therapeutic targeting of chromatin regulators could be used to extend lifespan and healthspan. This review describes the epigenetic regulation of lifespan in diverse model organisms, focusing on the role and mode of action of chromatin regulators that affect two epigenetic marks, trimethylated lysine 4 of histone H3 (H3K4me3) and trimethylated lysine 27 of histone H3 (H3K27me3), in longevity.

Figure 1. Phylogenetic analysis of C. elegans SET-2 and its homologs in yeast, flies and humans

Worm SET-2 is phylogenetically closer to SET1 in flies and SET1A/SET1B in humans than it is to Trithorax (MLL1/2) or Trithorax-related families (MLL3/4). The phylogenetic tree was constructed with ClustalW2 using full-length protein sequences.

Figure 2. Regulation of longevity by H3K4me3 modifiers in C. elegans

The ASH-2 H3K4me3 complex, consisting of ASH-2, SET-2, WDR-5 and possibly RbBp5, may promote aging by trimethylating H3K4. Note that the knock-down of the worm homologue of RbBP5, F21H12.1, has been shown to extend lifespan [84], although its impact on H3K4me3 is unknown. Conversely, the RBR-2 demethylase may promote longevity by demethylating H3K4me3.

Figure 3. Interplay between the germline and the soma in the regulation of longevity by ASH-2 complex deficiency

In adult worms, longevity by deficiencies in the ASH-2 complex requires an intact germline with continuous egg production. It is possible that unknown ‘pro-longevity’ signals are emitted from the fertilized eggs when ASH-2 complex members are deficient, thereby delaying aging of the soma. KD: knock-down.

Figure 4. Phylogenetic analysis of C. elegans RBR-2 and its homologs in yeast, flies and humans

The phylogenetic tree was constructed with ClustalW2 using full-length protein sequences.

Figure 5. Potential interactions between histone methylation marks in longevity

Several different histone methylation marks are regulated during aging in specific tissues (e.g. liver, brain) or the entire organism from worms to mammals. Histone regulators affect aging, at least in worms and flies. Complex interactions between different marks associated with active or repressed chromatin may participate in lifespan regulation.