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Developmental control of gene silencing

Award Number: R35GM151262
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: 09/22/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Developmental control of gene silencing - Project Summary Cells sharing a common genome transcribe a subset of their available genes to perform different functions. Polycomb-group (PcG) proteins contribute to cell specialization by binding and chemically modifying chromatin around lowly-transcribed genes to further reduce (“silence”) their expression. Although many PcG proteins have been identified, mystery surrounds the most interesting aspects of their function. The utility of silencing derives from its selective imposition. However, unknown mechanisms determine when silencing begins or ends during normal development. Furthermore, how PcG proteins epigenetically associate with different target genes in different cells is poorly understood. It is important to resolve these questions because silencing mistakes disrupt development and contribute to human cancers. The proposed research program uses a new model system, Drosophila nurse cell differentiation, and new genetic and genomic engineering tools to study how silencing initiation, maintenance, and reversal are developmentally regulated. The proposed model system overcomes technical limitations of studying silencing initiation in early embryos and embryonic cell cultures. A new proposed tool, termed UAS-gene swap, allows genetic substitution of PcG proteins with mutant versions in thousands of cells, and is compatible with sensitive molecular approaches like ChIPseq. The first proposed research direction will use UAS-gene swap to identify the interactions between PcG proteins and transcription factors that are important for establishing or preventing silencing at each potential Polycomb target gene. A second research direction will explore how a single PcG protein, Scm, is post-translationally regulated to time silencing initiation in differentiating nurse cells and other developmental contexts. Finally, a third research direction will use a highly- efficient genome engineering approach to explore how some Polycomb target genes are stably silenced while others are not. These diverse directions will significantly advance our understanding of how development regulates Polycomb silencing. They will also generate new tools to study gene expression control in developing organisms that will be valuable to the broader research community. Lastly, this research program may reveal potentially conserved mechanisms that regulate early embryonic development and prevent human cancers.


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 = $362,500 )
2025	2025	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	3	7/2/2025	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2024 ( Subtotal = $612,500 )
2024	2024	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	001	2	7/30/2024	NON-COMPETING CONTINUATION	$362,500
2024	2024	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	1	5/13/2024	SUPPLEMENT FOR EXPANSION	$250,000
														Subtotal = $612,500

Issue Date FY: 2023 ( Subtotal = $362,500 )
2023	2023	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	1	9/22/2023	NEW	$362,500
														Subtotal = $362,500

Grand Total All Awards = $1,337,500

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Developmental control of gene silencing

Award Number: R35GM151262

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: 09/22/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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