Berenice Benayoun - US grants

? DESCRIPTION (provided by applicant): 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.

A key hallmark of aging is an overall increase in genomic instability. Accumulating evidence has revealed widespread reactivation of transposable elements (TE) during aging across taxonomically-distant model organisms. Yet, the relationship between this aberrant reactivation and age-related functional decline is largely unknown, at the cellular, organ and organism levels. We hypothesize that the progressive loss of transposon repression contributes to the widespread age-related functional decline at the organismal level. The African turquoise killifish (Nothobranchius furzeri), an emerging naturally short-lived vertebrate model organism, provides a unique opportunity to investigate this link, and the investigators have previously developed a powerful genome-to-phenotype toolkit for this species. In this proposal, we propose to leverage the African turquoise killifish as a tractable short-lived model organism to rapidly interrogate the molecular and organismal impact of increased TE activity on vertebrate aging in vivo. To test our hypothesis, we propose (i) to characterize the repetitive element landscape in the genome of the African turquoise killifish and TE activation patterns, and (ii) to explore the impact of conserved changes in TE regulation with aging and age-related disease on the aging process. The completion of this project will advance the understanding of vertebrate aging. Ultimately, these findings will help define therapeutic targets for development of new treatments for age-associated diseases that have a heavy economic burden, and more importantly, cause extreme suffering to patients and their families.

Project summary The overarching goal of my lab is to understand understudied mechanisms of genomic regulation, and how they influence lifelong Vertebrate health and disease. In multi-cellular organisms, diverse cell types are characterized by specific genomic regulation patterns, and the precise control of these patterns is key not only for development, but also for cell/tissue homeostasis in adults. Indeed, loss of fine control in genomic regulation has been linked to disease (e.g. cancer, neurodegeneration) and age-related functional decline. An interesting and understudied family of genomic elements lies in dormant genetic parasites (e.g. transposons, also called ?jumping genes?). Although transposons can represent up to 80% of some eukaryotic genomes, they remain critically understudied, since they were historically dismissed as unimportant (i.e. ?junk DNA?), and their high copy numbers and repetitive nature pose unique technical challenges. Consistent with their potential impact in health and disease, the ability of cells to suppress transposon activity is disrupted with disease and with aging. In addition, accumulating evidence suggests that many aspects of biology and genomic regulation differ between males and females, including emerging data suggesting potential sex-dimorphism in transposon activity. However, how transposable elements are regulated throughout life in healthy somatic tissues and across biological sexes, and how they influence vertebrate health, remains largely unknown. Thus, we propose to decipher how transposons are controlled in healthy somatic cells (including in male vs. female cells), and how loss of that control could influence Vertebrate health and disease. To explore this question, my group will use a unique combination of ?omics? approaches, machine-learning, and experimental validation in animal models. We use two vertebrate models for their respective strengths: the laboratory mouse (e.g. powerful genetics, validated antibodies, etc.) and the African turquoise killifish, a naturally short-lived model organism I have helped develop (e.g. short generation time/lifespan, strain diversity, cost-effectiveness, etc.). First, we will decipher sex-dimorphic regulation of transposon activity, determining the impact of gonadal hormones vs. sex- chromosomes on such regulation. Second, we will use functional genomics to identify new regulators of transposon activity in somatic cells. Finally, we will evaluate the impact of transposon control in key somatic tissues and across sexes on lifelong vertebrate health using the naturally short-lived African turquoise killifish as a model. Ultimately, understanding the fine control of transposon in healthy cells will help devise strategies to prevent their misregulation in disease, by allowing us to maintain youthful and healthy genomic regulation landscapes. 1