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Mechanism of PRC2-mediated Gene Silencing during Cardiomyocyte Differentiation

Award Number: F30HL147499
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/15/2019
PERIOD OF PERFORMANCE END DATE: 05/14/2023

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Mechanism of PRC2-mediated Gene Silencing during Cardiomyocyte Differentiation - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$3,950 )
2024	2022	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	4	3/22/2024	NON-COMPETING CONTINUATION	-$3,950
														Subtotal = -$3,950

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	4	5/5/2022	NON-COMPETING CONTINUATION	$51,036
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	001	4	7/5/2022	NON-COMPETING CONTINUATION	$716
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	3	4/28/2021	NON-COMPETING CONTINUATION	$51,036
														Subtotal = $51,036

Issue Date FY: 2020 ( Subtotal = $34,763 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	2	5/18/2020	NON-COMPETING CONTINUATION	$34,763
														Subtotal = $34,763

Issue Date FY: 2019 ( Subtotal = $34,259 )
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	001	1	4/9/2019	NEW	$0
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Cardiovascular Diseases Research	000	1	4/9/2019	NEW	$34,259
														Subtotal = $34,259

Grand Total All Awards = $167,860

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Mechanism of PRC2-mediated Gene Silencing during Cardiomyocyte Differentiation

Award Number: F30HL147499

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/15/2019

PERIOD OF PERFORMANCE END DATE: 05/14/2023

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