Myocardial injury leads to scar formation and pathological fibrosis that has a significant impact on the development and progression of cardiac disease. Increasing evidence suggests alteration in the chromatin landscape of cells can exacerbate the extracellular matrix deposition and enhance disease progression. Chromatin alterations and fibrosis mediate several cardiac cellular changes, including scar formation, DNA damage, collagen deposition, and increased TGFB expression which are all disease-driving mechanisms during heart failure. Targeting epigenetic dependent fibrosis pathways is thus a promising strategy for the prevention and treatment after myocardial injury. The polycomb complex protein Bmi1, an epigenetic regulator, is associated with numerous biological functions including mediating DNA damage, cellular fate, and proliferation. However, there is currently a lack of understanding on how Bmi1 mediated epigenetic modifications affect adult heart function after injury. It was previously determined that Bmi1 modulates the epigenetic landscape of cardiac stem cells that mediates various molecular processes during a stress condition. In the present study, using a Bmi1 global and fibroblast specific knockout model, cardiac function was assessed through echocardiography using adult mice following cardiac injury. The loss of Bmi1 caused a significant decrease in heart function after injury, which was associated with increased fibrosis and DNA damage. Specifically, we found that the adult cardiac fibroblasts, isolated from the Bmi1 knockout model, had increased expression of pro-fibrotic genes including TGFB, aSMA, and Collagen1a1. Through multiomic sequencing, we found significant changes in the pathological fibrotic signaling pathways of TGFB, specifically with SMAD3 chromatin accessibility with the loss of Bmi1 epigenetic regulation. Concluding, Bmi1 epigenetic regulation mediates repair during pathological challenge by regulating adult cardiac fibroblasts and pathological fibrosis after cardiac injury. / Biomedical Sciences
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/8016 |
| Date | January 2022 |
| Creators | Kraus, Lindsay, 0000-0002-2871-1950 |
| Contributors | Mohsin, Sadia, Tilley, Douglas G., Scalia, Rosario, Koch, Walter J., McKinsey, Timothy A. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 81 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/7988, Theses and Dissertations |
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