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Mechanism and Regulation of Replication-Coupled Asymmetric Histone Incorporation in Drosophila Male Germline Stem Cells

Award Number: F31HD116510
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 09/02/2026
AWARD TERMINATION DATE: 10/27/2026

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Mechanism and Regulation of Replication-Coupled Asymmetric Histone Incorporation in Drosophila Male Germline Stem Cells - PROJECT SUMMARY Adult stem cells often divide asymmetrically to form one self-renewing stem cell and a differentiating daughter cell. This process is important to maintain homeostasis and produce cells with the correct fate. Because both daughter cells inherit the same genetic information, it is logically inferred that epigenetics play a key role in the differing cell fate decision. How epigenetic information is parsed in such an asymmetric way, however, is a significant question. One key epigenetic component are histones, and the Chen Lab previously discovered that histones are inherited asymmetrically with respect to preexisting (old) and newly synthesized (new) histones during the division of Drosophila male germline stem cells (GSCs), the first division of spermatogenesis. Old histones are preferentially inherited by the self-renewing GSC while new histones go to the differentiating cell. This suggests a potential mechanism by which asymmetric epigenetic information could be inherited in such a way to determine different cell fates in genetically identical daughter cells. Further, previous work in the lab has found that the histone asymmetry is established during S-phase by asymmetric histone partitioning at the DNA replication fork. This suggests S phase and DNA replication play a potentially large role in determining cell fate, but the precise coordination of factors determining when and where asymmetry occurs remains elusive. It is of interest to study how this asymmetry is established, which genomic regions are subject to asymmetry, and how this process can be regulated. Here I propose studying the role of two important and interconnected aspects impacting DNA replication: chromatin environment and replication timing. I have preliminary evidence that histone modifications associated with different types of chromatin (eg. euchromatin vs. facultative heterochromatin) incorporate at varying degrees of asymmetry in GSCs, suggesting histone recycling patterns are chromatin context-dependent. I propose systematically studying different histone modifications in GSCs and non-stem cells using single-molecule chromatin fibers combined with super resolution microscopy that can distinguish individual strands at the replication fork. Further, because timing during S phase is inherently linked to what type of chromatin is being replicated, I propose investigating the relationship between histone asymmetry and the DNA replication timing program. First, I plan to treat Drosophila testes with hydroxyurea, which will synchronize cells at the start of S phase. Measuring histone incorporation at different times following release into S phase will determine how different stages of S phase may experience different degrees of asymmetry. I also propose studying total histone asymmetry in fly lines lacking the master timing regulator Rif1 to determine if the DNA replication timing program is necessary for histone asymmetries to be established. The results of this project will contribute to a model of how histone asymmetry is achieved and what parts of the genome are most responsible for differential cell fate decisions following asymmetric epigenetic inheritance, paving the way for a better overall understanding of developmental biology, stem cell biology, and cell fate specification. This knowledge will be applicable to potentially many stem cell systems, as well as diseases associated with stem cell maintenance including stem cell cancers, premature aging, and fertility decline.


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: 2027 ( Subtotal = -$50,114 )
2027	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	3	10/27/2026	TERMINATION	-$50,114
														Subtotal = -$50,114

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	3	8/24/2026	NON-COMPETING CONTINUATION	$50,114
														Subtotal = $50,114

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	2	8/13/2025	NON-COMPETING CONTINUATION	$49,538
														Subtotal = $49,538

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	1	8/5/2024	NEW	$48,974
														Subtotal = $48,974

Grand Total All Awards = $98,512

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Mechanism and Regulation of Replication-Coupled Asymmetric Histone Incorporation in Drosophila Male Germline Stem Cells

Award Number: F31HD116510

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 09/02/2026

AWARD TERMINATION DATE: 10/27/2026

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