Research Overview

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The Greer lab is interested in how non-genetic information can be transmitted across generations. An increasing number of complex phenotypes, such as physical appearance, energy metabolism, psychological state, and longevity, have recently been shown to be regulated, in part, by epigenetic information. Epigenetics describes how gene expression changes occur without changes to the DNA sequence. Proteins, RNA molecules, or chemical modifications to histones or DNA can induce these epigenetic changes. How this information, which is not directly coded in our DNA, is passed from generation to generation is still unknown. Understanding the molecular determinants of stable epigenetic memory will provide insight into how environmental changes can affect the health and lifespan of not only the individual who experiences them, but also of their progeny. Our goals are to identify epigenetic inheritance phenotypes and to elucidate the mechanisms behind their transmission across generations.

We have previously identified chromatin-modifying enzymes that regulate complex transgenerational phenotypes in C. elegans, including longevity and fertility. Mutation of a histone H3 lysine 4 (H3K4) trimethylation complex regulates worm lifespan in both the generation in which the mutation occurs and in subsequent generations lacking the mutation. More recent work focuses on understanding how deletion of the C. elegans H3K4me2 demethylase, spr-5, leads to inherited accumulation of the euchromatic H3K4me2 mark and a progressive decline in fertility in successive generations. To investigate the underlying molecular mechanism behind progressive sterility of spr-5 mutant worms, we carried out an RNAi screen and identified both suppressors and enhancers of sterility. This screen led to a working model for how epigenetic changes in histone H3 methylation might be inherited to affect complex organismal traits. We also identified a novel form of DNA modifications in Metazoa, methylation of adenines (6mA), which may be responsible for stable transgenerational epigenetic inheritance.

Future studies will focus on experimentally testing this working model and 1) identification of the molecules that are inherited to regulate these transgenerational phenotypes, 2) how environmental cues alter an organism’s epigenetic landscape, and 3) determining how an epigenetic mark can be stably maintained or removed. We will address these questions using a combination of genetic, genomic and biochemical approaches in C. elegans and mammalian systems.

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  • Heritable Epigenics

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  1. Boulias K, Lieberman J, Greer EL. An Epigenetic Clock Measures Accelerated Aging in Treated HIV Infection. Mol Cell. 2016 04 21; 62(2):153-155. View abstract
  2. O'Brown ZK, Greer EL. N6-Methyladenine: A Conserved and Dynamic DNA Mark. Adv Exp Med Biol. 2016; 945:213-246. View abstract
  3. Greer EL, Becker B, Latza C, Antebi A, Shi Y. Mutation of C. elegans demethylase spr-5 extends transgenerational longevity. Cell Res. 2016 Feb; 26(2):229-38. View abstract
  4. Luo GZ, Blanco MA, Greer EL, He C, Shi Y. DNA N(6)-methyladenine: a new epigenetic mark in eukaryotes? Nat Rev Mol Cell Biol. 2015 Dec; 16(12):705-10. View abstract
  5. Greer EL, Blanco MA, Gu L, Sendinc E, Liu J, Aristizábal-Corrales D, Hsu CH, Aravind L, He C, Shi Y. DNA Methylation on N6-Adenine in C. elegans. Cell. 2015 May 07; 161(4):868-78. View abstract
  6. Greer EL, Beese-Sims SE, Brookes E, Spadafora R, Zhu Y, Rothbart SB, Aristizábal-Corrales D, Chen S, Badeaux AI, Jin Q, Wang W, Strahl BD, Colaiácovo MP, Shi Y. A histone methylation network regulates transgenerational epigenetic memory in C. elegans. Cell Rep. 2014 Apr 10; 7(1):113-26. View abstract
  7. Greer EL, Shi Y. What's the Mtrr with your grandparents? Cell Metab. 2013 Oct 01; 18(4):457-9. View abstract
  8. Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012 Apr 03; 13(5):343-57. View abstract
  9. Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP, Benayoun BA, Shi Y, Brunet A. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature. 2011 Oct 19; 479(7373):365-71. View abstract
  10. Maures TJ, Greer EL, Hauswirth AG, Brunet A. The H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent manner. Aging Cell. 2011 Dec; 10(6):980-90. View abstract
  11. Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS, Han S, Banko MR, Gozani O, Brunet A. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature. 2010 Jul 15; 466(7304):383-7. View abstract
  12. Greer EL, Banko MR, Brunet A. AMP-activated protein kinase and FoxO transcription factors in dietary restriction-induced longevity. Ann N Y Acad Sci. 2009 Jul; 1170:688-92. View abstract
  13. Greer EL, Brunet A. Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell. 2009 Apr; 8(2):113-27. View abstract
  14. Greer EL, Brunet A. Signaling networks in aging. J Cell Sci. 2008 Feb 15; 121(Pt 4):407-12. View abstract
  15. Greer EL, Brunet A. FOXO transcription factors in ageing and cancer. Acta Physiol (Oxf). 2008 Jan; 192(1):19-28. View abstract
  16. Greer EL, Dowlatshahi D, Banko MR, Villen J, Hoang K, Blanchard D, Gygi SP, Brunet A. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol. 2007 Oct 09; 17(19):1646-56. View abstract
  17. Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP, Brunet A. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem. 2007 Oct 12; 282(41):30107-19. View abstract
  18. Pondarré C, Antiochos BB, Campagna DR, Clarke SL, Greer EL, Deck KM, McDonald A, Han AP, Medlock A, Kutok JL, Anderson SA, Eisenstein RS, Fleming MD. The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulfur cluster biogenesis. Hum Mol Genet. 2006 Mar 15; 15(6):953-64. View abstract
  19. Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005 Nov 14; 24(50):7410-25. View abstract
  20. Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, Sharp JJ, Fujiwara Y, Barker JE, Fleming MD. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet. 2005 Nov; 37(11):1264-9. View abstract
  21. Gunshin H, Starr CN, Direnzo C, Fleming MD, Jin J, Greer EL, Sellers VM, Galica SM, Andrews NC. Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood. 2005 Oct 15; 106(8):2879-83. View abstract
  22. Beresford PJ, Zhang D, Oh DY, Fan Z, Greer EL, Russo ML, Jaju M, Lieberman J. Granzyme A activates an endoplasmic reticulum-associated caspase-independent nuclease to induce single-stranded DNA nicks. J Biol Chem. 2001 Nov 16; 276(46):43285-93. View abstract