Epigenetic regulatory mechanisms that govern cardiovascular development
2022-06
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Epigenetic regulatory mechanisms that govern cardiovascular development
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2022-06
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Cardiovascular disease (CVD) remains the number one cause of death in the United States and the World. The clinical outcomes of patients with heart failure, a form of CVD, remain poor because current clinical therapies do not address a critical feature of heart failure which is the loss of functional cardiac muscle. To decrease the morbidity and mortality in these patients, several strategies are being developed to replace the loss of functional cardiac muscle with new one. Two attractive strategies for treating CVD involve converting cardiac fibroblasts (reprogramming) into functional muscle or vascular cells and promoting cell cycle re-entry of adult cardiomyocytes following cardiac injury to replace the dead muscle. While the adult mammalian heart has limited regenerative potential following injury, the embryonic and neonatal mammalian heart has a remarkable regenerative capacity. Therefore, our goal for these studies was to define new factors and mechanisms that could enhance repair and regeneration in the adult mammalian heart. To this end, in this thesis, we identified novel epigenetic regulatory mechanisms that govern cardiovascular development, particularly within the vascular and cardiac muscle lineages. Our first finding is that we identified that ETV2 functions as a pioneer transcription factor that relaxes closed chromatin and regulates endothelial development. We did this by comparing engineered embryonic stem cell (mESCs) differentiation and reprogramming models (MEFs) with multi-omics techniques, we demonstrated that ETV2 was able to bind nucleosomal DNA and recruit BRG1. The recruitment of BRG1 led to the remodeling of chromatin around endothelial genes and helped to maintain an open configuration, resulting in increased H3K27ac deposition. Our second finding is that we discovered a signaling cascade where ETV2 regulates RHOJ expression during endothelial progenitor cell migration. We did this by combining computational genomics (RNAseq, ATACseq and ChIPseq) to discover that ETV2 regulates migratory pathways through the expression of RHOJ, particularly in developing endothelial progenitor cells (E7.75 and E8.5 mouse embryos and developing mESCs). Our third finding is that we identified FOXK1 as an essential transcriptional and epigenetic regulator of cardiovascular development. We used mESCs that lacked FOXK1 expression and discovered that in its absence, cardiac muscle development is significantly affected, both at the transcriptional and chromatin level. Mechanistically, we also discovered that FOXK1 represses Wnt signaling, particularly Wnt6, to promote the development of cardiac progenitor cells. ETV2 has the capacity to reprogram fibroblasts to mature vascular cells and our findings identified new mechanisms we can explore to better reprogram cardiac fibroblasts. Additionally, FOXK1 is a known cell cycle regulator and together with this newly identified role in the cardiovascular system, it becomes an attractive molecule that could be used to promote cell cycle re-entry of adult cardiomyocytes following ischemic injury. Altogether these studies provide exciting data for the field of cardiac regeneration but future studies will be needed in vivo to determine the potential benefit of these molecules following cardiac injury.
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University of Minnesota Ph.D. dissertation. 2022. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Daniel Garry. 1 computer file (PDF); 236 pages.
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Sierra Pagan, Javier. (2022). Epigenetic regulatory mechanisms that govern cardiovascular development. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/241708.
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