Deciphering FOXOs role in promoting longevity through transcriptional and epigenetic regulation

Brown, Abigail Kaywana-Ann

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Year:: 2021
Contributor:: Brown, Abigail Kaywana-Ann (creator); Webb, Ashley (Advisor); Freiman, Richard (Reader); Helfand, Stephen (Reader); Brossay, Laurent (Reader); Murphy, Coleen (Reader); Brown University. Department of Molecular Biology, Cell Biology and Biochemistry (sponsor)
Genre:: theses
Subject:: Transcription factors; epigenetics; Aging; Senescence; FOXO
Extent:: xvi, 149 p.

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Abstract:: Despite many studies linking FOXO factors to longevity, how these factors directly regulate aging particularly in humans, is not completely understood. The focus of this thesis is to understand of how FOXO3 functions mechanistically at the chromatin level in human cells to promote cellular homeostasis and healthy aging. Here, we take an integrated multi-omics approach to identify the chromatin-level mechanisms by which FOXO3 coordinates transcriptional programs in both healthy replicating cells and an aging model of senescence. In replicating cells, we find that FOXO3 functions as a pioneer factor in human cells, directly altering chromatin accessibility to regulate gene expression. Unexpectedly, FOXO3’s pioneer activity at many sites is achieved through a two-step process, in which chromatin accessibility is initially reduced, then transitions to an open conformation. The direct FOXO3 network comprises chromatin remodelers, including the SWI/SNF remodeling complex, which we find is functionally required for FOXO3 activity. We also identify a novel secondary network of activator protein-1 (AP-1) transcription factors deployed by FOXO3, which orchestrate a neuronal-specific subnetwork. Similarly, in senescent cells FOXO3 alters chromatin involved in maintaining cellular homeostasis, while AP-1 transcription factors alter regions promoting senescence. Together, this hierarchical FOXO3 pioneer network regulates key cellular processes including metabolism, proteostasis, epigenetics and proliferation, which must be tightly controlled under changing conditions that accompany aging.
Notes:: Thesis (Ph. D.)--Brown University, 2021

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Brown, Abigail Kaywana-Ann, "Deciphering FOXOs role in promoting longevity through transcriptional and epigenetic regulation" (2021). Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:8rut8u68/

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Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations

Theses and Dissertations for the Molecular Biology, Cell Biology, and Biochemistry department.
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