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Dissecting modular interaction of RNA with protein in chromatin

Award Number: R00GM137072
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Dissecting modular interaction of RNA with protein in chromatin - Project summary / Abstract The forefront of current RNA research centers on understanding the amazing complexity of this molecule. There is an expanding appreciation that the roles of RNA are multifaceted and extend far beyond its coding potential. RNA has the capacity for diverse structures, numerous modifications, and combinatorial interactions, and thus RNA is a foundational component for many complex regulatory networks. It is crucial to understand these networks from the level of individual molecular RNA interactions up through their effects on disease and development. In particular, many chromatin-associated proteins (CAPs) additionally interact with RNA, and may function in regulating gene expression by way of these RNA interactions. Previous studies, limited to identifying the RNAs bound by individual CAPs, did not consider combinatorial RNA binding. Here, I reveal that the CAP- RNA network contains clusters of RNAs that bind multiple proteins. Notably, Polycomb group and Trithorax group CAPs (EZH2 and WDR5, respectively) seem to interact with similar RNAs despite their opposing roles in chromatin modification. This suggests that EZH2- and WDR5- RNA interactions may affect or counter one another, and that this could manifest in altered chromatin states. I aim to elucidate how different CAP-RNA interactions affect one another and to characterize the relationship among RNA-binding of multiple CAPs. I hypothesize that RNA contains multiple elements, or modules, that interact with specific proteins, and that the functional readout of combinatorial interactions in a network can be understood by modular design principles of RNA. I propose the following aims to investigate this idea, particularly focusing on EZH2- and WDR5- RNA interactions: (1) development of a massively-parallel RNA assay (MPRNA) to identify RNA elements that bind to a particular protein, (2) investigating the modular principle using combinatorial synthesis of multiple RNA elements, (3) uncovering the underlying mechanism of RNA element organization and protein interaction. This approach will establish an interdisciplinary framework for studying RNA-centric networks, using both experimental and computational methods. It will reveal interaction principles and mechanisms of protein-RNA interactions, and examine functional consequences of these interactions. It will increase our understanding of RNA-based regulatory networks, particularly in the context of chromatin and CAP-mediated gene regulation. It may even provide insight into the control of Polycomb- and Trithorax- group complexes at sites of bivalent chromatin.


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: 2026 ( Subtotal = $0 )
2026	2023	LIEBER INSTITUTE INC	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	4	1/26/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $248,930 )
2023	2023	LIEBER INSTITUTE, INC.	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	4	9/13/2023	NON-COMPETING CONTINUATION	$248,930
														Subtotal = $248,930

Issue Date FY: 2022 ( Subtotal = $261,146 )
2022	2022	LIEBER INSTITUTE, INC.	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	3	9/1/2022	NON-COMPETING CONTINUATION	$248,930
2022	2021	LIEBER INSTITUTE, INC.	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	2	3/6/2022	EXTENSION WITH OR WITHOUT FUNDS	$12,216
														Subtotal = $261,146

Issue Date FY: 2021 ( Subtotal = $248,930 )
2021	2021	LIEBER INSTITUTE, INC.	855 N WOLFE ST STE 300	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	2	8/18/2021	EXTENSION WITH OR WITHOUT FUNDS	$248,930
														Subtotal = $248,930

Grand Total All Awards = $759,006

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Dissecting modular interaction of RNA with protein in chromatin

Award Number: R00GM137072

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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