Roles for Global Chromatin Structure in C. elegans Longevity

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DESCRIPTION (provided by applicant): Recent research has revealed many evolutionarily conserved genetic pathways important for longevity. In contrast, relatively little is known about the role of epigenetic changes in organismal aging. Epigenetic changes, such as altered levels or patterns of DNA methylation and post-translational histone modifications, have been observed in a variety of aging mammalian tissues and in aging human monozygotic twins. In yeast, worms, and flies, several histone modifying enzymes have been shown to play critical roles in determining longevity. Thus, emerging evidence points to a mechanistic link between chromatin structure and longevity. The goal of this proposal is to explore how global chromatin structure changes with aging in C. elegans. Because DNA methylation is nearly undetectable in C. elegans, post-translational modification of histones is likely the major regulatory mechanism of chromatin state in C. elegans. How the global chromatin state changes with age in C. elegans is completely unknown. In Aim 1, we propose to determine the genomic distribution and abundance of several major histone modifications in C. elegans of different age using the ChIP-seq technique. In Aim 2, we propose to comprehensively examine the transcriptional profiles of C. elegans at different age using the RNA-seq technique. Although the transcriptional profiles of C. elegans through aging have previously been examined using microarray studies, microarray studies have multiple limitations and the RNA-seq technique is generally considered to provide a much more comprehensive view of gene expression profiles. We plan to compare the ChIP-seq and the RNA-seq results to identify, with high confidence, the genes that show age-dependent changes, even for genes that are expressed at low levels and those that only show subtle expression changes. Comparing the ChIP-seq and the RNA-seq results will also reveal age-dependent changes in alternatively spliced transcripts, as well as novel transcripts that have not been previously annotated, including non- coding RNAs. These changes are likely not revealed previously due to the limitations of previous gene expression studies. Comparing the ChIP-seq and RNA-seq data will also provide insights into the chromatin state that help specify age-dependent mRNA expression changes. Some of the age-dependent histone modification and mRNA expression changes may represent valuable molecular markers of aging. Importantly, some of these changes may point to regulatory factors that contribute to longevity determination. Our proposed research will be the first to globally profile how chromatin state is impacted as C. elegans age. Considering the high degree of conservation between the genetic pathways that modulate longevity in C. elegans and mammals, we anticipate that some of the epigenetic mechanisms that impact C. elegans longevity will also be conserved in mammals. PUBLIC HEALTH RELEVANCE: This application proposes to investigate how aging is impacted by certain special features of the genome that are stably inherited through multiple rounds of cell division, but do not involve changes in the DNA sequence. These epigenetic features often involve specific decorations of the DNA or the proteins that help compact DNA, and their proper maintenance is critically important for cells and organisms to maintain certain characteristics. To date, very little is known about how these epigenetic features affect aging and age-dependent diseases, and our research proposes to use two different comprehensive approaches to examine how changes in these features affect longevity in the powerful model system soil nematode. Our proposed research may lead to future therapeutic development that aims to improve healthy aging and alleviate age-dependent diseases.