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Dissertation
lncRNA H19/Let7b/EZH2 axis regulates somatic cell senescence
Doctor of Philosophy (Ph.D.), Drexel University
May 2022
DOI:
https://doi.org/10.17918/00001359
Abstract
Long non-coding RNAs (lncRNAs) regulate diverse cellular processes and are associated with many age-associated diseases. However, the function of lncRNAs in cellular senescence remains largely unexplored. H19 is a highly conserved maternally imprinted gene that is critical in controlling embryonic growth. Loss of H19 results in fetal overgrowth, while elevated H19 occurs in human cancers. In this study, we characterize the role of lncRNA H19 in senescence. We show that H19 levels decline as cells undergo senescence and depletion of H19 results in premature senescence via the H19/let7b/EZH2 axis. Specifically, we show that during exposure to overwhelming cellular stress, repression of H19 is triggered by the loss of CTCF and prolonged activation of p53 as part of the senescence pathway. Mechanistically, the loss of H19 drives senescence due to its negative regulation of let7b. Loss of H19 allows let-7 targeting of EZH2. Enzymatically, EZH2 (Enhancer of zeste homolog 2) is responsible for methylation of H3L4, a repressive histone modification, and the reduction in EZH2 establishes the senescence phenotype through the loss of H3K27me3 repressive marks at key senescence gene loci. We further show that H19 is regulated by prolonged treatment with rapamycin, an mTOR inhibitor, maintains lncRNA H19 levels, and prevents the decline in EZH2 to delay the onset of cellular senescence. Overall, the results reveal a novel role for lncRNA H19 in maintaining the balance between sustained cell growth and the onset of senescence.
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Details
- Title
- lncRNA H19/Let7b/EZH2 axis regulates somatic cell senescence
- Creators
- Manali Potnis
- Contributors
- Christian Sell (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xii, 153pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991019104706704721