OVERALL ABSTRACT Epigenetics is a critical determinant of aging and longevity, and senescence is a key driver of age-associated pathologies. Our program is leading efforts to understand the epigenetics of cell senescence and aging. Our overall hypothesis is that the epigenome is inherently dynamic/plastic to provide for flexible regulation, and during aging, this dynamic epigenome undergoes a loss of overall integrity. This loss of epigenome integrity, in turn, contributes to a secondary cascade of cell and tissue signaling events that also exacerbate aging, for example Senescence-Associated Secretory Phenotype (SASP) in senescent cells, a cause of ?inflamm-aging?. We have coined the term ?chromostasis? for the process whereby cells and tissues attempt to manage their dynamic/plastic epigenome to maintain epigenome integrity, transcriptional fidelity and, hence, promote healthy aging and longevity. The current P01 grant period was highly successful, as measured by our publications (56 total), collaborative efforts (20 collaborative publications), and our contributions to the fields of aging and epigenetics (104 publications since initial funding in 2008). Our specific major accomplishments in the current grant period are: (1) We uncovered dramatic changes to the epigenomic landscape within senescent human cells, some of which also occur in aged and diseased tissues. We discovered mechanisms underlying this altered epigenomic landscape, including disruption heterochromatin and the first example of a nuclear substrate of autophagy. (2) We discovered new mechanisms for activation of the SASP in senescent cells, and pioneered new small molecule/drug-based approaches to inhibit the SASP and promote healthy aging, including MLL and HDAC inhibitors. (3) We discovered a DNA methylation clock in mouse, and showed its slowing by diverse prolongevity interventions. (4) We dissected the structure and function of the HUCA (HIRA/UBN1/CABIN1/ASF1a) histone chaperone complex, a key mediator of histone dynamics in senescent cells, and defined the molecular basis of HUCA?s histone H3.3 variant selectivity. (5) We found age-correlated alterations in conserved chromatin factors that lead to inappropriate cryptic transcription from gene bodies, and showed this to be a novel cause of aging. In the renewal of this PO1, we will (1) leverage multi-disciplinary discovery platforms to uncover mechanisms underlying deficient chromostasis, (2) determine relevance of altered chromostasis in mouse/human aging, and (3) dissect mechanisms underlying the secondary pro-aging signaling events and identify pharmacological approaches to block these processes to promote healthy aging.
OVERALL NARRATIVE The epigenome is a rich target for strategies to promote healthy aging. First, approaches that promote epigenetic maintenance ? chromostasis ? can foster phenotypic stability and suppression of age-associated degeneration. Second, targeted epigenetic inhibitors of pro-aging cellular phenotypes, such as SASP, can also promote healthy aging. This collaborative project will explore both avenues to promote healthy aging.
|Lin-Shiao, Enrique; Lan, Yemin; Coradin, Mariel et al. (2018) KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis. Genes Dev 32:181-193|
|Dou, Zhixun; Berger, Shelley L (2018) Senescence Elicits Stemness: A Surprising Mechanism for Cancer Relapse. Cell Metab 27:710-711|
|Ray-Gallet, Dominique; Ricketts, M Daniel; Sato, Yukari et al. (2018) Functional activity of the H3.3 histone chaperone complex HIRA requires trimerization of the HIRA subunit. Nat Commun 9:3103|
|Berson, Amit; Sartoris, Ashley; Nativio, Raffaella et al. (2017) TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling. Curr Biol 27:3579-3590.e6|
|Bonini, Nancy M; Berger, Shelley L (2017) The Sustained Impact of Model Organisms-in Genetics and Epigenetics. Genetics 205:1-4|
|Dou, Zhixun; Ghosh, Kanad; Vizioli, Maria Grazia et al. (2017) Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550:402-406|
|Mews, Philipp; Donahue, Greg; Drake, Adam M et al. (2017) Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 546:381-386|
|Yang, Ting-Lin B; Chen, Qijun; Deng, Jennifer T et al. (2017) Mutual reinforcement between telomere capping and canonical Wnt signalling in the intestinal stem cell niche. Nat Commun 8:14766|
|Cole, John J; Robertson, Neil A; Rather, Mohammed Iqbal et al. (2017) Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions. Genome Biol 18:58|
|Feng, Zijie; Wang, Lei; Sun, Yanmei et al. (2017) Menin and Daxx Interact to Suppress Neuroendocrine Tumors through Epigenetic Control of the Membrane Metallo-Endopeptidase. Cancer Res 77:401-411|
Showing the most recent 10 out of 83 publications