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Various epigenetic factors were found to be necessary for the implementation and inheritability of an increased life span caused by mild heat stress in C. elegans.
Epigenetics is the study of heritable phenotypes that don’t involve changes in the DNA sequence, and it manifests primarily through the mechanisms of: DNA methylation, histone modifications, or small RNAs (Dupont et al. 2009). The phenomenon of these epigenetic changes being passed down through the generations is known as transgenerational epigenetic inheritance, or TEI (Wan et al. 2021). Epigenetic changes during pregnancy have been implicated in a wide range of health issues later in life, such as cancer, coronary heart disease, stroke, or diabetes (Dupont et al. 2009). These effects highlight the importance of further research to deepen our understanding of epigenetic mechanisms.
Various stresses (excess heat, osmotic stress, etc.) that an organism faces have been shown to result in physiological changes, an effect that has recently been discovered to be caused by epigenetic changes in the organism (Seong et al. 2011). Though some responses to stress cause issues for the organism once things return to normal, others impart lasting benefits (such as an increase in life span, for example). These beneficial responses are known as hormetic responses (Wan et al. 2021). Of particular interest to this study was a hormetic response seen across several species: mild heat stress resulting in increased life spans and stress resistance (Hercus et al. 2003).
Caenorhabditis elegans is a model organism that has been used in the field of genetics since 1974 (Brenner 1974). It is particularly useful for studies of TEI thanks to its short reproductive cycles, large broods, easily manipulated germ line, and evolutionarily conserved epigenetic mechanisms (Wan et al. 2021). Additionally, C. elegans has been shown to undergo the hormetic response of heat stress resulting in increased life spans and stress resistance. While high temperature induced TEI effects have been observed in C. elegans, Wan et al. attempted to discover whether the same was true for the hormetic response to heat, and if so, what mechanisms were behind the effect.
Before anything else, the authors first investigated whether the life span increase caused by mild heat shock was an inheritable effect. They did this by exposing an individual C. elegans to 35° C for 1 hour, then tracking the lifespans of both itself and seven generations of its offspring. They found, by comparing these lifespans to that of control (unheated) worms, that the increased lifespan caused by mild heat stress persisted through five generations, before disappearing from the lineage. They also showed, by heat shocking either the mother or father individually, that this hormetic heat stress response can be transmitted through either the sperm or the egg.
Having established its inheritability, the authors then sought to understand the underlying mechanisms involved. The authors utilized GFP-tagged proteins to show that an increase in autophagy, which had been associated with the hormetic heat stress response, was also seen in two generations of the heat-shocked worm’s descendants, confirming its inheritability. Using a similar method, they also found that the HLH-30 transcription factor was translocated to the nucleus of heat stressed worms and their progeny.
Using various methods to stop their expression (mutant strains and RNA interference) the authors identified three genes that are necessary for the hormetic heat response: hsf-1, daf-12, and daf-16. By stopping the expression of these genes at specific times (ie, only in the parents), they also found that only daf-16 was necessary for the hormetic response to be passed down to the offspring of an individual.
One of the mechanisms of epigenetic change I mentioned earlier was histone modifications. By using specific mutant strains which lack the ability to make certain histone modifications, the authors found that the histone modification H3K9me3 was not required for the hormetic response itself, but was required for the response to be passed to the next generation. They confirmed this using various sequencing techniques. Through similar methods, the authors also discovered that N6-mA DNA modification was required for both the hormetic response and its inheritance. Using immunoprecipitation and dot blot analysis, they further found that N6-mA was colocalized with H3k9me3. In general, the authors found several factors that were required for the hormetic heat response to occur, but only daf-16, H3K9me3, and N6-mA modified DNA were required for the response to be inherited.
While this study has contributed an incredible amount to our understanding of the hormetic heat stress response of C. elegans, and its ability to be inherited, several questions still remain. How, specifically, are daf-16, H3K9me3, and N6-mA modifications interaction on a molecular level to cause this epigenetic effect? Additionally, this specific response has also been seen in drosophila and human fibroblasts (Hercus et al. 2003), so a similar study focused on one of those subjects may be interesting.
Anthony Eckdahl is a senior biology major at Davidson College. Contact him at: aneckdahl@davidson.edu
References
Brenner S., 1974 The Genetics of CAENORHABDITIS ELEGANS. Genetics 77: 71–94. https://pubmed.ncbi.nlm.nih.gov/4366476/
Dupont C., D. R. Armant, and C. A. Brenner, 2009 Epigenetics: Definition, Mechanisms and Clinical Perspective. Semin Reprod Med 27: 351–357. https://doi.org/10.1055/s-0029-1237423
Hercus M. J., V. Loeschcke, and S. I. S. Rattan, 2003 Lifespan extension of Drosophila melanogaster through hormesis by repeated mild heat stress. Biogerontology 4: 149–156. https://doi.org/10.1023/A:1024197806855
Seong K.-H., D. Li, H. Shimizu, R. Nakamura, and S. Ishii, 2011 Inheritance of Stress-Induced, ATF-2-Dependent Epigenetic Change. Cell 145: 1049–1061. https://doi.org/10.1016/j.cell.2011.05.029
State P., 2006 An adult C. elegans worm. https://www.flickr.com/photos/pennstatelive/29983729810/in/photostream/
Wan Q.-L., X. Meng, W. Dai, Z. Luo, C. Wang, et al., 2021 N6-methyldeoxyadenine and histone methylation mediate transgenerational survival advantages induced by hormetic heat stress. Science Advances 7: eabc3026. https://doi.org/10.1126/sciadv.abc3026
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