Paper: Epigenetics of Lifespan

Regina Terry
BIO 293 – Cell Biology
Fall 2017

          Epigenetics is a topic within the field of biology that involves studying changes in the expression of genes (in other words, the switching on and off of genes) while the genes themselves are not changed. As described in two articles published by the Nature International Journal of Science, one on July 15, 2010 and one on November 17, 2011 and posted on Blackboard, a group of scientists studied epigenetics by looking at the effects of epigenetic changes on the lifespan of a number of organisms – more specifically, how chromatin changes affect longevity of an organism’s lifespan. This is interesting because of what we might see emerge in things like aging and the lifespans for future generations. Now, one item of importance that is mentioned in the above-mentioned articles is H3K4, which is a specific lysine and a specific histone. Lysine is an important amino acid and can be found in histones, which arrange DNA strands into nucleosomes and are a big part of chromatins. H3K4 stands for lysine 4 of histone 3 (one of the main types of histones). Histone methylation is where a methyl group (or methyl groups) is added to proteins of histones. The methylation of H3K4 can occur as either mono-methylation, di-methylation, or tri-methylation (“mono” for 1 methyl group being added, “di” for 2, and “tri” for 3). Each of these can have different effects on gene activity. Mono- methylation predominantly activates gene expression (increasing gene transcription), while di- methylation and tri-methylation vary more in how they affect gene activity (though they usually silence gene expression, decreasing gene transcription). If methylation of H3K4 is reduced, gene expression is turned on, which leads to more gene transcription.

          Looking back at the article “Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans” from the Nature International Journal of Science, we see what resulted in these studies. The genes SET-2, SET-4, SET-6, SET-9, SET-15, BLMP-1, and ASH-2 appear to be important based on Figure 1(a) on page 2 of the article “Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans,” which shows the amount of change in percentage in the average lifespan of worms given RNAi when certain genes are examined. ASH-2 (which is a methyltransferase that converts di-methylation of H3K4 to tri-methylation of H3K4) and SET-2 (a lysine-specific methyltransferase domain) look to be the most important out of the above-mentioned group of genes. These two genes, along with the WD40-repeat protein WDR-5, make up the ASH-2 complex and, at least in worms like C. elegans, work together to manage lifespans of C. elegans and trimethylate H3K4. Figures 1(b) and 1(e) on page 2 of the article “Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans,” we see that RNAi (and direct gene mutation for WDR-5) was used to take out ASH-2, WDR-5, and SET-2 when mono-methylation, di-methylation, and tri-methylation of H3K4 occurs. When RNAi (and direct gene mutation for WDR-5) knock out ASH-2, SET-2 and WDR-5, tri- methylation is lost (ASH-2) or lowered (WDR-5 and SET-2), di-methylation is decreased (WDR-5) or slightly increased (ASH-5 and SET-2), and mono-methylation stays about the same. These do correspond to changes in lifespan. When the mutated WDR-5 is knocked out (a.k.a. turned off), lifespan becomes longer. Lifespan also increases when ASH-2 and SET-2 are turned off. In other words, when methylation stops (a.k.a. when the methyl groups are taken out), lifespan increases. As we see in the provided articles from the Nature International Journal of Science, ASH-2 is a methyltransferase, meaning it adds methyl groups (CH3) to H3K4. The gene RBR-2 is a demethylase of histones, which removes methyl groups from histones like H3K4. RBR-2 acts as a counterbalance to the impacts of the ASH-2 complex, and these two coordinate the tri-methylation of H3K4 and lifespan. In terms of methylation, RBR-2 swaps and undos what ASH-2 does, and RBR-2 and the ASH-2 complex regulate lifespan. When RBR-2 is knocked out, H3K4 methylation decreases and lifespan is shortened.

          The article “Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans” from the Nature International Journal of Science discusses how epigenetic effects on lifespan are inherited by future generations. The worm species Caenorhabditis elegans was used for studying here again. The changes seen above in H3K4 methylation appear to continue for up to 4 or 5 generations, so they are heritable. How many generations of descendants inherit these changes depend on the gene and how it is changed (if at all). WDR-5 (part of the ASH-2 complex) being reduced diminishes H3K4 tri-methylation, which results in a longer lifespan in C. elegans. According to this article (“Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans”), the study described indicates that lifespan was still longer through the fourth generation of descendants of a set of WDR-5 parents, though only if there is a WDR-5 deficiency in the parents’ generation. This was similar for SET-2, where lifespan is extended for generations of descendants up to the fourth generation, but not the fifth generation. Similar to WDR-5, a decrease or removal of the gene ASH-2 (by RNAi) in the worms decreased tri- methylation of H3K4, lengthening worms’ lifespan. If this decrease of ASH-2 occurs enough in the parents’ generation, this extension of lifespan persists for 3 generations of descendants. The fourth generation of descendants did not have this change in lifespan. It was observed that a reduction or lack of RBR-2 does not have an effect on descendant generations’ lifespan like the above-mentioned gene changes do. Tests were not done to see if any genes shortened lifespan.

          In conclusion, to extend lifespan, one would want to target the genes that make up the ASH-2 complex, SET-2, ASH-2, and WDR-5. These have a significant effect on extending lifespan when decreased. One gene to avoid could be RBR-2, as this helps regulate a normal lifespan instead of increasing or decreasing it. Other genes may have some effect, such as SET-9, SET-15, and UTX-1, but may have not have as much effect as the genes in the ASH-2 complex. As we have seen here, the flatworm C. elegans was used for the epigenetic testing of genes to study lifespan increase. This may work in humans, as the methylation of histones has been found to be important for mammals’ development and keeping their stem cells able to create different kinds of cells (pluripotent). In addition, the ASH-2 complex is found in mammals, and ASH-2 transforms H3K4 di-methylation into H3K4 tri-methylation. WDR-5 is also found in mammals and is a protein found working with ASH-2 in mammals for mono-, di-, and tri-methylation of H3K4. SET-2 is comparable to the gene(s) SET1A/SET1B.

References Cited

Fink, C. and Kraynak, J. (n.d.). Epigenetics and Bipolar Disorder. [online] dummies: A Wiley Brand. Available at: http://www.dummies.com/health/mental-health/epigenetics-and-bipolar-disorder/ [Accessed 28 Nov. 2017].

Greer, E., Maures, T., Hauswirth, A., Green, E., Leeman, D., Maro, G., Han, S., Banko, M., Gozani, O. and Brunet, A. (2010). Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. [online] Nature International Journal of Science. Available at: https://www.nature.com/articles/nature09195 [Accessed 28 Nov. 2017].

Greer, E., Maures, T., Ucar, D., Hauswirth, A., Mancini, E., Lim, J., Benayoun, B., Shi, Y. and Brunet, A. (2011). Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. [online] Nature International Journal of Science. Available at: https://www.nature.com/articles/nature10572 [Accessed 27 Nov. 2017].

What is Epigenetics?. (2013). A Super Brief and Basic Explanation of Epigenetics for Total Beginners. [online] Available at: https://www.whatisepigenetics.com/what-is-epigenetics/ [Accessed 28 Nov. 2017].

What is Epigenetics?. (n.d.). Epigenetics: Fundamentals, History, and Examples. [online] Available at: https://www.whatisepigenetics.com/fundamentals/ [Accessed 28 Nov. 2017].

Bhasin, M., Reinherz, E. and Reche, P. (2006). Recognition and Classification of Histones Using Support Vector Machine. [online] Journal of Computational Biology. Available at: http://online.liebertpub.com/doi/abs/10.1089/cmb.2006.13.102 [Accessed 27 Nov. 2017].

BPS Bioscience. (2017). Demethylase(s). [online] Available at: http://bpsbioscience.com/demethylase [Accessed 27 Nov. 2017].

Encyclopedia Britannica. (1998). Restriction enzyme : Biology. [online] Available at: https://www.britannica.com/science/restriction-enzyme#ref271348 [Accessed 27 Nov. 2017].

GeneNames. (n.d.). Gene Family: Histones. [online] Available at: https://www.genenames.org/cgi-bin/genefamilies/set/864 [Accessed 27 Nov. 2017].

Pubchem: Open Chemistry Database. (2004). L-lysine. [online] Available at: https://pubchem.ncbi.nlm.nih.gov/compound/L-lysine#section=Top [Accessed 27 Nov. 2017].

Revolution Health & Wellness. (n.d.). What is Methylation and Why Should You Care?. [online] Available at: http://www.revolutionhealth.org/what-is-methylation-and-why-should-you-care/ [Accessed 27 Nov. 2017].

What is Epigenetics?. (n.d.). Histone Modifications. [online] Available at: https:// http://www.whatisepigenetics.com/histone-modifications/ [Accessed 28 Nov. 2017].

Greer, E., Maures, T., Hauswirth, A., Green, E., Leeman, D., Maro, G., Han, S., Banko, M., Gozani, O. and Brunet, A. (2010). Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. 1st ed. [PDF] Nature International Journal of Science (Macmillan Publishers Limited), pp.1-7. Available at: ODU Blackboard OR https://www.nature.com/articles/nature09195 [Accessed 26 Nov. 2017].

Steel, Dr. C. (2017). Video: Explanation of Figures. Available at: ODU Blackboard

Greer, E., Maures, T., Ucar, D., Hauswirth, A., Mancini, E., Lim, J., Benayoun, B., Shi, Y., and Brunet, (2011). Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. 1st ed. [PDF] Nature International Journal of Science (Macmillan Publishers, Inc.), pp.1-9. Available at: ODU Blackboard OR https://www.nature.com/articles/nature10572 [Accessed 26 Nov. 2017].

Steel, Dr. C. (2017). Powerpoint-Epigenetics of Lifespan. Available at: ODU Blackboard

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Author: rterry293cellbio

I am a student at ODU studying Biology.

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