My overarching goal is to understand the epigenomic regulation of aging. Functional decline of organs and tissues is a hallmark of aging, which is accompanied by changes in gene expression levels and chromatin modifications across cell types. However, the impact of these changes on aging is still largely unclear. Recent work suggests that aging results in a loss of transcriptional networks integrity and may be linked to changes in transcriptional variability (or cell-to-cell noise). The regulation of transcriptional variability has important consequences on cell-fate decisions, embryo patterning and stress response, but its regulation by chromatin and role in aging have remained elusive. We have recently identified a new type of chromatin domain, broad domains marked by the H3K4me3 modification, which preferentially mark genes important for cell identity/function. These broad H3K4me3 domains do predict high gene expression but increased transcriptional consistency (i.e. low variability). Interestingly, our pilot analyses suggest that broad H3K4me3 domains can be aberrantly modified during aging. Given the loss of transcriptional precision with age, regulation of H3K4me3 breadth may be a mechanism by which consistent gene expression is ensured despite environmental fluctuations. Such consistency in gene expression may be particularly important to maintain cell and tissue homeostasis throughout life. However, the mechanisms involved in broad H3K4me3 domains deposition and how they regulate transcriptional consistency in young vs. old cells is still unknown. The goal of my proposal is to explore the mode of action of this chromatin signature on transcriptional consistency and its dysregulation with age. Specifically, I hypothesize that the deposition of broad H3K4me3 domains is directed by lineage-specific transcription factors and general regulators of transcription, and that they promote transcriptional consistency of marked genes, a process compromised during aging. My experiments will use adult neural progenitor cells as a model system. These regenerative cells can produce new neurons important for certain forms of learning and memory, but decline during aging. Using a combination of epigenomics, cell biology and innovative computational modeling, this project will i) characterize the regulation of H3K4me3 breadth, ii) tease apart the link between H3K4me3 breadth and transcriptional consistency, and iii) investigate aberrant remodeling of H3K4me3 domains with age. Ultimately, this work will give insights into the epigenetic regulation of aging and lay the groundwork for rejuvenation of aged cells back to a youthful healthy state. Finally, the career development and training components of this proposal will provide key elements for my successful transition to an independent career and my ability to integrate knowledge of the aging field with cutting-edge experimental and computational strategies to improve the understanding of general mechanisms that are compromised during aging.

Public Health Relevance

Understanding how complex regulatory processes deteriorate during aging should help delay age-related diseases. Transcriptional precision is an important aspect of gene expression regulation, which affects how cells respond to environmental fluctuations and becomes misregulated during aging. This study aims at understanding the mechanisms underlying transcriptional variability in young cells and during aging and should ultimately provide a molecular handle to rejuvenate dysfunctional aged cells to a youthful healthy functional state, which should have key implications for delaying age-related diseases.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Career Transition Award (K99)
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National Institute on Aging Initial Review Group (NIA)
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Guo, Max
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Stanford University
Schools of Medicine
United States
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