Monday, June 30, 2025 6/30/2025

Characterizing the RNA-mediated recruitment of histone deacetylases to chromatin

Award Number: F30CA278005
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Characterizing the RNA-mediated recruitment of histone deacetylases to chromatin - PROJECT SUMMARY Global histone deacetylation is linked to many types of cancer and is controlled by histone deacetylases (HDACs). Although HDAC inhibitors are widely used in cancer treatment, their activity does not target specific HDAC isoforms nor specific genes and therefore results in significant side effects for patients. Thus, there is a pressing need to target HDAC activity in a highly precise, gene-specific manner to develop safer and more effective treatments. The overall objective of this proposal is to understand how HDACs are recruited to specific genome regions. Because HDACs do not possess intrinsic DNA binding activity, they are thought to be recruited to chromatin through interactions with DNA binding proteins, though this mechanism has not been fully explored. Recently, our lab and others identified that the SHARP RNA-binding protein directly interacts with the Xist long noncoding RNA (lncRNA) to specifically recruit HDAC3 to the future inactive X chromosome (Xi). In this way, the Xist-SHARP/SMRT/HDAC3 repressive complex deacetylates histones and silences gene expression on the Xi. Our lab has also demonstrated that SHARP localizes to many nuclear sites (beyond the Xi) in an RNA-dependent manner, raising the question of which additional RNAs recruit it (along with HDAC3) and to what specific genomic locations. Notably, nearly all human HDACs associate within multi-protein complexes containing SHARP and other RNA-binding proteins, suggesting that this mechanism of RNA-guidance may extend beyond SHARP and Xist. I hypothesize that HDAC complexes are recruited by RNAs to achieve specificity to their various regulatory targets throughout the nucleus. First, I will determine which SHARP-RNA interactions are functionally important by genetically perturbing the SHARP binding sites of candidate RNAs. I will then measure effects on gene expression and if HDAC3 activity is required for these effects (Aim 1). Second, I will comprehensively identify RNA-binding proteins associated with other cancer-associated HDACs and define their in vivo RNA binding sites. I will then determine which protein-bound candidate RNAs from this screen are regulated in an HDAC-dependent manner (Aim 2). The proposed research has the potential to transform our understanding of RNAs and RNA- binding proteins as central regulators in organizing chromatin modifications by HDACs in both normal and cancerous cell states.


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: 2025 ( Subtotal = $54,538 )
2025	2025	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Cancer Research Manpower	001	3	5/30/2025	NON-COMPETING CONTINUATION	$564
2025	2025	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Cancer Research Manpower	000	3	4/14/2025	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Cancer Research Manpower	000	2	5/27/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Cancer Research Manpower	000	1	5/8/2023	NEW	$52,694
														Subtotal = $52,694

Grand Total All Awards = $161,206

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Characterizing the RNA-mediated recruitment of histone deacetylases to chromatin

Award Number: F30CA278005

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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