Extensive work has established that the beneficial, anti-cancer function of the p16INK4a tumor suppressor mechanism makes counteracting negative contributions to mammalian aging. Age associated increases of p16INK4a in this model repress the proliferative and regenerative potential of some organ compartments. Though many of the findings demonstrating this counterbalancing effect of p16INK4a were observed in murine models, recent genome wide association studies (GWAS) have independently and repeatedly found associations with single nucleotide polymorphisms (SNPs) proximal to p16INK4a and numerous age-associated conditions, such as frailty, type 2 diabetes, atherosclerotic disease (including myocardial infarction, ischemic stroke, intracranial aneurism and aortic aneurism), and endometriosis. These variants are in strong linkage with haplotypes that overlap ANRIL, a long non-coding RNA of unknown biological function. We have previously demonstrated that ANRIL produces alternatively spliced mRNA and, unexpectedly, circular RNA species, and moreover that expression of some of these species correlate to GWAS identified SNPs. In this work we intend to investigate these species using genome wide and focused approaches.
In aim 1 we will assess the association between previously identified polycomb group repressor complex members (SUZ12, CBX7 and MOV10) and circular ANRIL.
In aim 2 we will develop and apply a method for genome wide identification of endogenous circular RNA transcripts. Together these will elucidate the role of the little studied circular RNA constituent f the mammalian transcriptome and develop our understanding of the role of important non-coding RNAs relevant to numerous diseases of aging.
Numerous genome wide association studies have identified relationships between diseases of aging, including coronary artery disease, diabetes and frailty, and a single locus of the human genome located on chromosome 9. Though this genomic locus contains multiple genes important to cancer and aging, it is unknown how variants in some individuals can lead to disease. In this proposal, we aim to examine the molecular interactions of linear and novel circular RNA products of this genetic locus and their possible role in age related disease.
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