PROJECT SUMMARY
The experience of our ancestors has important consequences for our own health. Studies in humans
and animal models have shown that stress or trauma experienced in one generation can affect the cognition,
behavior, and physiology of subsequent descendants for multiple generations. However, the mechanisms of
transgenerational inheritance have proven challenging to study, partially due to the scarcity of epigenetic
phenotypes that can be traced through multiple generations. Thus, we have developed a unique model for
transgenerational epigenetic inheritance in the nematode Caenorhabditis elegans that allows us to link
molecular changes with phenotypic effects over dozens of generations. Our long-term goal is to leverage
this model to understand how chromatin landscapes shape gene expression, cell fate, and physiology.
In our cells, genomes are packaged into chromatin, in which DNA is wrapped around cores of histone
proteins. Modifications are added and removed from histones, regulating access to DNA and therefore, gene
expression. The addition of two methyl groups to lysine 9 of histone 3 (H3K9me2) is associated with gene
repression, while addition to lysine 4 of the same histone (H3K4me) is associated with gene activation. We
discovered that a mutation in either WDR-5, which belongs to an H3K4 methylating complex, or a mutation in
JHDM-1, a putative demethylase for H3K9me2, causes the gradual, genome-wide accumulation of repressive
H3K9me2. This accumulation causes a gradual lifespan extension in both mutants: wdr-5 mutants acquire
longevity after twenty generations, while jhdm-1 mutants acquire longevity after eight generations. We will use
this model of transgenerational epigenetic inheritance to probe the consequences caused by the
inappropriate inheritance of repressive H3K9me2.
We hypothesize that generational changes in repressive H3K9me2 affect gene expression and
organismal physiology to impact health and extend lifespan. This proposal combines unbiased genomic
analyses with classical genetic approaches in two Specific Aims: 1. Identify which specific pathways respond to
the transgenerational accumulation of repressive H3K9me2 by examining health, gene expression, and
chromatin accessibility; and 2. Determine how H3K9me2 accumulation genetically interacts with the known
lifespan-extending pathway of lipid metabolism using epistasis analysis. Our approach offers two main
advantages: as self-fertilizing hermaphrodites, homozygous populations of C. elegans are genetically identical,
allowing us to distinguish epigenetic traits from genetic ones; and importantly, C. elegans can survive
perturbations to epigenetic inheritance that cause embryonic lethality in other animals. The mechanisms of
epigenetic regulation are highly conserved among all eukaryotes, including nematodes and mammals.
Therefore, our proposed research will provide fundamental insight into how the inheritance of chromatin
landscapes affects gene expression in human health and disease.
