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H3K9me3-based gene silencing and cellular identity

Award Number: R35GM148115
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: 02/02/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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H3K9me3-based gene silencing and cellular identity - The overarching goal of the research in the Salz lab is to understand the regulatory logic and molecular mechanisms underlying cell fate choice and commitment. As loss of cell fate leads to developmental disorders, cancer, and infertility, a comprehensive understanding of the many different mechanisms used by cells to establish and secure their chosen fate is essential. Our current work is focused on the female/male fate choice in the Drosophila germline, where we have found that female germ cell identity depends on the permanent repression of testes genes. This proposal builds on our exciting, published work showing that discrete gene- specific blocks of repressive H3K9me3 chromatin silences key regulatory genes normally expressed in the male germline. The repressive H3K9me3 histone modification is best known for its role in constitutive heterochromatin formation and the repression of transposable elements, but recent work in organisms ranging from fission yeast to humans (including our own) reveals that H3K9me3 peaks are also associated with the silencing of protein- coding genes normally expressed in other tissues. Although these emerging studies identify H3K9me3-mediated gene silencing as a conserved and vital strategy for securing cell fate, there is very little information about how H3K9me3 is recruited to protein-coding genes. And there is no information about whether the mechanism governing H3K9me3-mediated gene silencing in one tissue is generalizable to other tissues. These gaps limit our understanding of H3K9me3's role in silencing lineage inappropriate genes in normal development and may therefore impinge on our ability to diagnose and treat disease. The research proposed in this MIRA application will build on our foundational work in the Drosophila germline to fill these gaps in knowledge. Using the powerful genetic approaches and exciting modern technologies available in the fly, we expect our work in female germ cells to accelerate the discovery of new genes and molecular mechanisms relevant to H3K9me3-medidated gene silencing. Our new studies in the larval brain will extend these findings by determining whether somatic cells use an analogous silencing mechanism. When complete, these studies will provide fundamental insights into one of the least understood epigenetic mechanisms governing cell fate choice and commitment.


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 = $402,500 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Biomedical Research and Research Training	001	3	1/17/2025	NON-COMPETING CONTINUATION	$362,250
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Biomedical Research and Research Training	002	3	8/5/2025	NON-COMPETING CONTINUATION	$40,250
2025	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Biomedical Research and Research Training	000	2	11/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $402,500

Issue Date FY: 2024 ( Subtotal = $402,500 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Biomedical Research and Research Training	000	2	1/4/2024	NON-COMPETING CONTINUATION	$362,250
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Biomedical Research and Research Training	001	2	6/24/2024	NON-COMPETING CONTINUATION	$40,250
														Subtotal = $402,500

Issue Date FY: 2023 ( Subtotal = $422,500 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Biomedical Research and Research Training	000	1	2/2/2023	NEW	$422,500
														Subtotal = $422,500

Grand Total All Awards = $1,227,500

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H3K9me3-based gene silencing and cellular identity

Award Number: R35GM148115

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: 02/02/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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