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Leveraging genetic divergence to uncover mechanisms of genomic organization

Award Number: F32GM163363
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2026
PERIOD OF PERFORMANCE END DATE: 09/29/2027

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Leveraging genetic divergence to uncover mechanisms of genomic organization - Project Summary As all the cells in an organism share the same DNA, it is how the genome is structured and interpreted that gives rise to the diversity of cell types. To allow for proper gene expression, the genome must be organized into active and inactive nuclear compartments. Active regions are gene rich and accessible to transcription-factor binding. By contrast, repetitive DNA must be localized to inactive nuclear compartments, as failure to permanently silence repetitive loci leads to developmental defects and cancer. Because nuclear organization is essential for proper development, it is established during the earliest stages of embryogenesis. The embryo is initially transcriptionally quiescent and must establish chromatin architecture de novo during the maternal-to-zygotic transition (MZT). This project will leverage the rapidity of Drosophila embryogenesis to determine how the nucleus is partitioned. We demonstrated that the transcription factor GAGA factor (GAF) is non-uniformly distributed in the nucleus and is required for establishing both the active and inactive nuclear compartments. In active compartments, GAF is essential for promoting accessible chromatin and activating gene expression. Simultaneously, GAF is concentrated in foci at GA-rich satellite repeats to promote establishment of constitutive heterochromatin and silence expression of repetitive loci. By determining the features that allow GAF to perform two contradictory functions in the same nucleus at the same time, we will elucidate the fundamental molecular mechanisms that partition the genome. We will modulate the ratio of GAF to the GA-rich regions it binds by generating hybrid Drosophila embryos and determine the effects on nuclear organization and gene expression. In a complementary aim, we will use proximity ligation to identify cofactors that function with GAF in distinct subnuclear compartments. Together, our work will use evolutionary, biochemical, and genetic approaches to determine how the interactions between fast-evolving repeats and the factors that bind them segregate the nucleus into active and silenced regions. Our proposed research is significant because it will investigate how repetitive elements can affect the genome in trans by redistributing regulatory factors with implications for normal development and cancer.


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 = $76,300 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Biomedical Research and Research Training	000	1	4/1/2026	NEW	$76,300
														Subtotal = $76,300

Grand Total All Awards = $76,300

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Leveraging genetic divergence to uncover mechanisms of genomic organization

Award Number: F32GM163363

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2026

PERIOD OF PERFORMANCE END DATE: 09/29/2027

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