Epigenetic regulation of aging in C. elegans

 

The plasticity of aging and the regulation of lifespan by environmental interventions such as dietary restriction raise the possibility that reversible epigenetic modifications that affect chromatin states play a pivotal role in regulating longevity. Histone methylation is a reversible modification associated with active or repressed chromatin that was known to be crucial during development and in maintaining stem cell pluripotency. However, the importance of histone methylation in organismal lifespan was unclear.

To determine whether histone methylation regulates lifespan, we performed a targeted RNAi screen in C. elegans using fertile worms. We identified the ASH-2 COMPASS complex, which trimethylates histone H3 at lysine 4 (H3K4), as a regulator of lifespan in C. elegans. We found that deficiencies in members of the ASH-2 complex, including the H3K4 methyltransferase SET-2, 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 – a mark associated with active chromatin – is detrimental for longevity (Greer et al, Nature, 2010). Intriguingly, ASH-2 and RBR-2 act in the germline to regulate lifespan and control genes involved in lifespan determination (Greer et al, Nature, 2010). More recently, we also identified regulators of the repressive epigenetic mark H3K27me3 as playing a role in worm aging (Maures et al, Aging Cell, 2011). Unlike H3K4me3 regulators, H3K27me3 regulators affect longevity in a manner that does not depend on the germline. H3K27me3 drastically drops during aging. Our findings are exciting because they identify a crucial role for histone methylation in organismal aging and reveal that there is an interaction between the germline and the soma for the regulation of lifespan by chromatin regulators (Han and Brunet, Trends in Cell Biology, 2012).

A fundamental question is whether epigenetic changes that affect lifespan in the parental generation can still impact the lifespan of the subsequent generations even when the factors that led to these changes are no longer present. While some evidence of transgenerational epigenetic inheritance for simple traits exist, very little is known about the transgenerational inheritance of acquired complex traits. Understanding the epigenetic memory of longevity between generations has the potential to profoundly impact the current paradigm on the inheritance of complex diseases and will also have a broad impact on our understanding of epigenome reprogramming. We recently made the surprising discovery that mutations in specific regulators of trimethylated lysine 4 on histone H3 (H3K4me3) in parents lead to lifespan extension in descendants for up to three generations, even after the initial mutation is no longer present (Greer et al, Nature 2011). Studying epigenetic memory of a complex trait has the potential to revolutionize our understanding of the inheritance of integrative phenotypes, including aging and longevity.

 

Publications

Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS, Han S, Banko MR, Gozani O and Brunet A. (2010) Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature, 466: 383-387. Abstract PDF

Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP, Benayoun BA, Shi Y and Brunet A (2011). Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature (Article), 479: 365-371. Abstract PDF Supplementary information

Maures TJ, Greer EL, Hauswirth AG and Brunet A (2011). H3K27 demethylase UTX-1 regulates
C. elegans lifespan in a germline-independent, insulin-dependent, manner. Aging Cell, 10: 980-990.
Abstract PDF

Han S and Brunet A (2012) Histone methylation makes its mark on longevity. Trends in Cell Biology, 22:42-49. Abstract PDF

 

Specific projects

Regulation of the FOXO transcription factor network

Importance of pro-longevity genes in aging neural stem cells

Role of FOXO transcription factors in cognitive function

Mechanisms underlying longevity by dietary restriction in C. elegans: role of the energy sensor AMPK

Unbiased screen to identify novel AMPK substrates in mammalian cells

Epigenetic regulation of aging in C. elegans

Development of the African killifish N. furzeri as a genetic model to identify the genetic architecture of vertebrate aging