Project 2: Local and global epigenome regulation of senescence and aging

Studies in animal models reveal that genetic differences and somatic mutations underlie longevity, but that non-genetic contributions play a major role. Numerous observations, including from this PPG point to epigenetic alterations in chromatin as having a crucial role both in senescence and in aging. However, key questions remain, in particular, what are the driving epigenetic mechanisms that underlie cellular phenotypes that characterize senescence and aging? Our hypothesis is that normal chromatin processes include a drive toward stability or homeostasis of the epigenome, a process our PPG coined as “chromostasis”, however, chromostatic maintenance is imperfect and thus during aging leads to tissue deterioration and disease. Hence, genetic approaches and pharmaco-therapeutics to enhance mechanisms that maintain epigenome stability are prominent across all collaborative projects of this PPG and in this Project 2. During previous funding we uncovered chromatin alterations during mammalian senescence and aging, indeed we provided pioneering observations of altered histone acetylation during aging. Our results, with collaborative findings in this PPG, broadly support the concept of declining chromostasis during aging manifesting in epigenome dysregulation, with dire functional consequences. Our recent observations include (1) acquisition of new strong regulatory enhancers (“super-enhancers”) and hyper-connected enhancer “cliques” driving genes of senescence; (2) enhancer-to-promoter conversion within gene introns leading to “cryptic” transcriptional initiation; (3) evidence that metabolic pathways intersect with epigenetic pathways. To uncover the mechanisms and physiological importance of these new chromatin regulators and pathways in aging, we will carry out the following aims. 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. Overall, the proposed collaborative 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 intervene in age-related diseases and to extend healthy lifespan. Project Number: 1P01AG092325-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: SHELLEY BERGER | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $401,404 | Activity Code: P01 | Study Section: Special Emphasis Panel[ZAG1 ZIJ-6 (J1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11096620