Transgenerational epigenetic inheritance of longevity in C. elegans

by Greer et. al. 2011

Ray XiaoJake GianuzziAbbie Ho

Important Concepts/Key Terms-C. elegans as a model organism-Brief review of chromatin and histone-’Reprogramming’ the Epigenome

-Main purpose of the paper-WDR-5-SET-2-ASH-2

C. eleganswhy is it a good model organism?-relatively inexpensive-remain transparent throughout their life cycle-C. elegans are very fertile-short maturation period-first multicellular organism that has complete sequenced genomes

Chromatin & Histone-Chromatin is the combination or complex of DNA and proteins that make up the contents of the nucleus of a cell.

-Functions: 1) to package DNA into a smaller volume to fit in the cell 2) to strengthen the DNA to allow mitosis 3) to prevent DNA damage 4) to control gene expression and DNA replication

Chromatin & Histone-Histones are the primary protein components of chromatin that compact the DNA-Histones are modified by various post-translational modification to alter DNA packing

Reprogramming the Epigenome“..changes in chromatin states in the parental generation could be

incompletely reprogrammed in the next generation and thereby affect lifespan of descendants.” -Abstract

What is meant by ‘reprogrammed’?

Why is ‘reprogramming’ important (to the organism and its progeny)?

-It is important that epigenome-wide reprogramming does not happen during a mature organisms life so that its epigenome is ‘remembered’.

-It is important that most epigenetic marks of a mature individual are irrelevant to the next generation, the slate is wiped clean to allow gametic epigenomes to endow the capacity to differentiate into all cell types of a fully developed organism.

-Removal of (most) epigenetic marks established during the development of a mature organism

Objectives

-The results show that deficiencies in H3K4me3 chromatin modifiers ASH-2, WDR-5, SET-2 in the parental generation extend the lifespan of descendants for several generations.

What do they study? (What molecule or property of molecules)

H3K4me3 in C. Elegans

What do they alter experimentally to study this molecule/property?

Perturbation of the H3K4me3 regulatory complex (ASH2, WDR5, SET2) only in the parental generation --could it affect longevity of progeny across generations?

Key PlayersCOMPASS: A heptameric protein complex, consists of SET1: responsible for the bulk of H3K4 methylation - and associated proteins

SET2: Histone methyltransferase

WDR-5: a conserved regulatory component of ASH-2

ASH-2: a component for the conversion of H3K4me2 to H3K4me3

The Active MarkH3K4me3 is an ‘active mark’, associated with active chromatin, and its excess is detrimental to longevity.

How could this be achieved? (i.e. molecular mechanism?)

Chromatin modifier WDR-2Figure 1.

Chromatin modifier SET-2Figure 2.

Fig3

-Firstly, because it is a viable method for gene suppression in culture and in vivo, and because synthetic dsRNA can selectively & robustly induce suppression of specific genes of interest.-Secondly, because ash-2 deletion mutations have been shown ASH2 to be essential, with its mutation resulting in embryonic lethality

Why the dropoff in lifespan increase at F4 rather than F5 as with wdr-5 and set-2?

How was the ash-2 knockdown different than that of wdr-5 and set-2?-RNAi was used for knockdown, as opposed to gene knockout, of ash-2.

Why was this experiment done this way?Any suggestions for why the ‘possible degradation product’ of ash-2 is most abundant in the control P0 organisms? (See 3C)

Fig4

What do Fig4a,b show us?

What do Fig4c,d show us?

Other Longevity Regulators Effect

figure 5

H3K4me3 Expression between mutant and WT

figure 6

Some Statistics

Hierarchical Clustering - Genes with similar expression patterns are grouped together and are connected by a series of branches

Hypergeometric Probability - Drawing without replacement in finite population size.

Principal component analysis - Charting a set of observed variables into a set of linear uncorrelated values.

figure 6

Possible Mechanisms for Epigenetic Memory

Possible Mechanisms for Epigenetic Memory

1. By H3K4me3 alone, loss of epigenetic memory due to H3K4me3 itself expression threshold reached.

2. Other chromatin modifiers marks that are related to H3K4me3.

3.Inherited non-coding RNA that eventually degrades below functional level.

4. Other possible mechanisms? What do you think?

Evolution PerspectiveCan this transgenerational effect of longevity be interpreted as an adaptation?

Can you come up with a theory that fits the results of the experiment?

Evolution PerspectiveConsider H3K4me3 is conserved through most organisms, does transgenerational epigenetic memory, in terms of lifespan alteration, apply to other species as well?

ReferencesXiao, Yu, Cecile Bedet, Valerie J Robert, Thomas Simonet, Steve Dunkelbarger, Cedric

Rakotomalala, Gwen Soete, Hendrik Korswagen, Susan Strome, and Francesca Palladino. 2011. Caenorhabditis Elegans Chromatin-associated Proteins SET-2 and ASH-2 Are Differentially Required for Histone H3 Lys 4 Methylation in Embryos and Adult Germ Cells. Proceedings of the National Academy of Sciences of the United States of America. 108, no. 20: 8305-8310.

Greer, Eric, Travis Maures, Anna Hauswirth, Erin Green, Dena Leeman, Geraldine Maro, Shuo Han, Max Banko, Or Gozani, Anne Brunet, and NATURE PUBLISHING GROUP. 2010. Members of the H3K4 Trimethylation Complex Regulate Lifespan in a Germline-dependent Manner in C. Elegans. NATURE. 466, no. 7304: 383.

Greer, Eric, Travis Maures, Duygu Ucar, Anna Hauswirth, Elena Mancini, Jana Lim, Berenice Benayoun, Yang Shi, and Anne Brunet. 2011. Transgenerational Epigenetic Inheritance of Longevity in Caenorhabditis Elegans. Nature. 479, no. 7373: 365-371.

Benayoun, Berenice, and Anne Brunet. 2012. Epigenetic Memory of Longevity in Caenorhabditis Elegans. Worm. 1, no. 1: 77-81.