Saturday, October 23, 2021
10/23/2021
Project Summary Cardiomyocytes require precise gene regulation programs to prevent pathophysiology. Upregulation of cardiac remodeling genes results in cardiomyocyte hypertrophy and decreased heart function. While much is known about the transcription factors that drive cardiomyocyte specific gene expression, we have a limited understanding of how histone posttranslational modifications regulate cardiomyocyte development and maintenance. Polycomb Repressive Complex 2 (PRC2) is a histone modifying complex that silences gene expression by tri-methylating lysine 27 on histone H3. Conditional knockout studies show the absence of PRC2, during mouse heart development, results in upregulation of cardiomyocyte specific transcription factors and cardiac hypertrophy. However, there is a lack of mechanistic understanding regarding how PRC2 regulates cardiomyocyte specific genes. Emerging evidence demonstrates that human PRC2 is recruited to chromatin through an interaction with a set of accessory proteins known as AEBP2 and PCL proteins. This proposal will utilize PRC2 separation-of-function mutations to test the hypothesis that the interaction between PRC2 and these accessory proteins is necessary for regulating cardiomyocyte specific genes and for preventing cardiomyocyte hypertrophy. High-throughput sequencing and immunocytochemistry approaches will be used to determine whether AEBP2 or PCL proteins is/are responsible for maintaining the transcriptional profile and phenotype of cardiomyocytes in a PRC2 dependent manner. Furthermore, live-cell single-molecule imaging will be used to define how AEBP2 and PCL proteins affect the chromatin-binding dynamics of PRC2 throughout cardiomyocyte differentiation. The experiments in this proposal represent a critical step toward uncovering the mechanism of PRC2 mediated gene-silencing in cardiomyocytes, a mechanism that is central to normal heart development and function. Training Plan Summary: The proposed research will be completed in the University of Colorado Boulder Biochemistry Department, located in the multidisciplinary BioFrontiers Biotechnology building. The applicant will draw from local expertise in the fields of cardiomyocyte biology, computational biology, chromatin biology, and transcriptional regulation to develop into an independent physician-scientist that is well versed in mechanisms of gene regulation. The applicant’s training plan includes taking coursework, receiving individual mentorship, attending conferences, giving oral presentations, and preparing/submitting manuscripts.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
