Local and global epigenome regulation of senescence and aging

Project summary Chromatin and epigenetic information influences gene expression without changing the underlying genome and can provide cellular memory through cell division. Epigenetic mechanisms are under intense investigation for regulation of age-related changes in phenotype, including age-related changes in gene expression and disease states. Studies in animal models reveal that genetic differences underlie longevity, but that non- genetic contributions play a major role, such as, famously, calorie restriction. Numerous findings, including seminal observations from our lab, reveal numerous epigenetic alterations in chromatin as eukaryotes age, and, importantly, are drivers of aging. A major theme in our work is that the epigenome is maintained by an active process of chromatin homeostasis—that healthy aging involves efficient epigenome maintenance. This process is imperfect, hence, in aging chromatin disorganization underlies tissue deterioration and organismal death. Interventions to enhance epigenome maintenance are prominent in our research both to investigate function and to advance as future therapeutics. Here, we explore mechanisms of local and global epigenetic changes in driving senescence and aging- associated phenotypes. We show (1) acquisition of new strong regulatory enhancers (“super-enhancers”) and hyper-connected enhancer-promoter “cliques” drive gene expression during senescence; (2) enhancer-to- promoter conversion within gene introns leads to inappropriate “cryptic” transcriptional initiation within genes; (3) evidence that metabolic enzymes “moonlight” in the nucleus and intersect with epigenetic pathways. Our results broadly support the hypothesis that changes in chromatin regulation and prominently loss of chromatin homeostasis leads to dysregulation of the epigenome and the nucleus, accompanied by cellular and organismal functional decline. In Aim 1, we will investigate how enhancers are rewired during senescence and aging with a focus on large enhancer communities or cliques. We will decipher how cliques are formed and identify major transcription factors that drive their formation. In Aim 2, we will investigate how cryptic transcription is initiated within genes, and transcription factors and epigenetic enzymes that regulate this process in senescence and aging. Further, our data suggest a link between cryptic initiation and cliques, to be investigated in detail. In Aim 3 we focus on a nuclear metabolic enzyme, PHDX, that interacts with the histone acetyltransferase KAT7 to activate senescence-associated secretory phenotypes. Here we will uncover how PDHX rewires the epigenome to promote senescence phenotypes and will identify whether disruption of the PDHX/KAT7 interface can be an intervention for age-related diseases. Overall, our research will reveal chromatin mechanisms—connecting to metabolic mechanisms—underlying stability of the epigenome in longevity, with the potential to discover new therapeutic targets to disrupt age-related diseases and to extend healthy lifespan.