Epigenetics: A memory of longevity

Worms with increased levels of the epigenetic mark H3K9me2 have a longer lifespan that can be passed down to future generations.
  1. Felicity Emerson
  2. Cheng-Lin Li
  3. Siu Sylvia Lee  Is a corresponding author
  1. Cornell University, United States

It is commonly accepted that genetic sequences coded within DNA are passed down through generations and can influence characteristics such as appearance, behavior and health. However, emerging evidence suggests that some traits can also be inherited ‘epigenetically’ from information that is independent of the DNA sequence.

One of the ways characteristics may be epigenetically passed down is through the temporary modification of histone proteins which help to package DNA into the cell. Histones are adorned with chemical marks that can regulate how and when a gene is expressed by changing how tightly the DNA is wrapped. These marks are typically removed before genetic information is passed on to the next generation, but some sites escape erasure (Heard and Martienssen, 2014; Kelly, 2014; Miska and Ferguson-Smith, 2016).

It has previously been reported that genetic mutations in an enzyme complex called COMPASS increase the lifespan of tiny worms called Caenorhabditis elegans (Greer et al., 2010). This complex acts on histones and creates a chemical mark called H3K4me, which is typically associated with less compact DNA and higher gene expression. When these mutants mate with wild-type worms they generate descendants that no longer have COMPASS mutations. Although these wild-type offspring recover normal levels of H3K4me, they still inherit the long-lived phenotype which they sustain for several generations (Greer et al., 2011). This observation suggests that an epigenetic mechanism that is independent from the gene mutation causes this inherited longevity. Now, in eLife, David Katz and co-workers at the Emory University School of Medicine in Atlanta – including Teresa Lee as first author – report a possible mechanism to explain how this longer lifespan is epigenetically inherited across multiple generations (Lee et al., 2019).

Previous work showed that one of the COMPASS complex mutants, known as wdr-5, has increased levels of another histone mark called H3K9me2 (Kerr et al., 2014). This epigenetic mark generally promotes DNA compaction and appears to antagonize the action of H3K4me. This led Lee et al. to question whether the elevated levels of H3K9me2 may be important for the inheritance of this extended lifespan in wdr-5 worms.

To test their hypothesis, the team carefully monitored the levels and patterns of H3K9me2 in the mutants. Surprisingly, they found that homozygous wdr-5 mutants, which had descended from ancestors carrying one copy of the mutated wdr-5 gene and one wild-type copy for multiple generations, did not live for longer than their non-mutant counterparts. This indicates that the mutation carried by wdr-5 worms did not immediately cause a lifespan change. However, future generations of worms that maintained the homozygous wdr-5 mutation had an increasingly longer lifespan, suggesting that the accumulation of an epigenetic signal across generations promotes longer living. These late generation wdr-5 mutants had higher levels of H3K9me2, and they were able to pass on this extended longevity to their progeny following mating with wild-type worms as previously reported (Greer et al., 2011).

Next, Lee et al. manipulated the levels of H3K9me2 to see how this affected the phenotype of the late generation, long-lived wdr-5 worms. First, they blocked the gain in H3K9me2 levels in the mutants by introducing a defective version of an enzyme called MET-2 which normally promotes the addition of H3K9me2 (Figure 1). As a result, neither the wdr-5 mutants nor their descendants experienced a longer lifespan. Lee et al. reasoned that if higher H3K9me2 levels are responsible for longevity, then increasing the amount of H3K9me2 by a different mutation should result in the same phenotype as the wdr-5 worms. They found that worms with defects in the enzyme JHDM-1, which is predicted to remove H3K9me2, not only lived longer but also passed on this trait to their wild-type progeny for several generations. Together, these data strongly suggest that increased H3K9me2 levels contribute to extended longevity and its inheritance.

Certain epigenetic changes are linked to the inheritance of extended lifespans in worms.

Top: The WDR-5 enzyme helps to place the H3K4me mark (green), which promotes gene expression, on proteins called histones (brown circle) that package DNA (grey ribbon). In parallel, the MET-2 enzyme places the H3K9me2 mark (red), which represses gene expression. The two marks functionally antagonize each other. An enzyme called JHDM-1 is predicted to remove H3K9me2. Bottom: Worms with mutations in wdr-5 or jhdm-1 (left) that have low levels of H3K4me (green arrow), also show higher levels of H3K9me2 (red arrow) and an increased lifespan (grey arrow). When these long-lived mutants are mated to wild-type worms with a normal lifespan, their genetically wild-type offspring (right) are still long-lived for several generations (grey arrow). These worms show normal levels of H3K4me mark (green square) and regions of sustained increase in H3K9me2 (red arrow) inherited from their mutant ancestors.

Image credit: Cheng-Lin Li.

To build on these findings, Lee et al. explored where the H3K9me2 marks were deposited in the genomes of the worms. As expected, long-lived wdr-5 and jhdm-1 mutants have more H3K9me2 marks spread across their genomes. Critically, Lee et al. found that specific genes in the wild-type offspring of jhdm-1 mutants had higher levels of H3K9me2. These results are intriguing and suggest that increasing H3K9me2 levels in certain genes may be the key to passing on this long living phenotype to future generations. Exciting future investigations will be to identify all the gene regions associated with the inherited increase in H3K9me2, and to understand how changes to DNA packaging and gene expression in those regions influence longevity.

A handful of previous studies in C. elegans have demonstrated that specific histone modifications can be inherited across generations (Katz et al., 2009; Kerr et al., 2014; Kaneshiro et al., 2019). However, the paper by Lee et al. is the first to tie together the inheritance of a histone mark to longer lifespan. H3K9me2 is an evolutionarily conserved histone mark which is known to preserve spatial organization during cell division in organisms ranging from humans to worms (Poleshko et al., 2019). Going forward, it will be interesting to study whether H3K9me2 also participates in how traits are inherited across multiple generations in mammals.

References

Article and author information

Author details

  1. Felicity Emerson

    Felicity Emerson is in the Biomedical and Biological Sciences Program at the Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7151-1711
  2. Cheng-Lin Li

    Cheng-Lin Li is in the Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2501-6565
  3. Siu Sylvia Lee

    Siu Sylvia Lee is in the Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States

    For correspondence
    sylvia.lee@cornell.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5225-4203

Publication history

  1. Version of Record published: January 24, 2020 (version 1)

Copyright

© 2020, Emerson et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,057
    Page views
  • 267
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Felicity Emerson
  2. Cheng-Lin Li
  3. Siu Sylvia Lee
(2020)
Epigenetics: A memory of longevity
eLife 9:e54296.
https://doi.org/10.7554/eLife.54296

Further reading

    1. Chromosomes and Gene Expression
    Daniël P Melters, Keir C Neuman ... Yamini Dalal
    Research Article

    Chromatin accessibility is modulated in a variety of ways to create open and closed chromatin states, both of which are critical for eukaryotic gene regulation. At the single molecule level, how accessibility is regulated of the chromatin fiber composed of canonical or variant nucleosomes is a fundamental question in the field. Here, we developed a single-molecule tracking method where we could analyze thousands of canonical H3 and centromeric variant nucleosomes imaged by high-speed atomic force microscopy. This approach allowed us to investigate how changes in nucleosome dynamics in vitro inform us about transcriptional potential in vivo. By high-speed atomic force microscopy, we tracked chromatin dynamics in real time and determined the mean square displacement and diffusion constant for the variant centromeric CENP-A nucleosome. Furthermore, we found that an essential kinetochore protein CENP-C reduces the diffusion constant and mobility of centromeric nucleosomes along the chromatin fiber. We subsequently interrogated how CENP-C modulates CENP-A chromatin dynamics in vivo. Overexpressing CENP-C resulted in reduced centromeric transcription and impaired loading of new CENP-A molecules. From these data, we speculate that factors altering nucleosome mobility in vitro, also correspondingly alter transcription in vivo. Subsequently, we propose a model in which variant nucleosomes encode their own diffusion kinetics and mobility, and where binding partners can suppress or enhance nucleosome mobility.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Maikel Castellano-Pozo, Georgios Sioutas ... Enrique Martinez-Perez
    Short Report Updated

    The cohesin complex plays essential roles in chromosome segregation, 3D genome organisation, and DNA damage repair through its ability to modify DNA topology. In higher eukaryotes, meiotic chromosome function, and therefore fertility, requires cohesin complexes containing meiosis-specific kleisin subunits: REC8 and RAD21L in mammals and REC-8 and COH-3/4 in Caenorhabditis elegans. How these complexes perform the multiple functions of cohesin during meiosis and whether this involves different modes of DNA binding or dynamic association with chromosomes is poorly understood. Combining time-resolved methods of protein removal with live imaging and exploiting the temporospatial organisation of the C. elegans germline, we show that REC-8 complexes provide sister chromatid cohesion (SCC) and DNA repair, while COH-3/4 complexes control higher-order chromosome structure. High-abundance COH-3/4 complexes associate dynamically with individual chromatids in a manner dependent on cohesin loading (SCC-2) and removal (WAPL-1) factors. In contrast, low-abundance REC-8 complexes associate stably with chromosomes, tethering sister chromatids from S-phase until the meiotic divisions. Our results reveal that kleisin identity determines the function of meiotic cohesin by controlling the mode and regulation of cohesin–DNA association, and are consistent with a model in which SCC and DNA looping are performed by variant cohesin complexes that coexist on chromosomes.