Wednesday, December 31, 2025 12/31/2025

Elucidating the role of SUMO ligase Su(var)2-10 in piRNA-guided transcriptional silencing and repressive chromatin formation

Award Number: R00HD099316
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Elucidating the role of SUMO ligase Su(var)2-10 in piRNA-guided transcriptional silencing and repressive chromatin formation - Project Summary: Heterochromatin refers to the compacted and transcriptionally suppressed chromatin state that typically includes repeat-rich regions near chromosomal arm ends, transposable elements (TEs), as well as some genes. Heterochromatin plays important architectural and regulatory roles, and its misregulation leads to aberrant gene expression and chromosome instability associated with cancers, aging and in germ cells, embryonic lethality and sterility. Large fraction of heterochromatin from yeast to humans is marked by histone H3 lysine 9 trimethylation (H3K9me3). H3K9me3 is deposited by histone mark “writer” complexes which can be recruited to genomic targets by DNA binding proteins or small RNA guides. Many aspects of heterochromatin establishment and maintenance in the cell and in development remain poorly understood. Heterochromatin regulation is the central focus of this proposal. In germ cells, Piwi proteins and associated Piwi-interacting small RNAs (piRNAs) guide a writer complex to install the H3K9me3 mark and induce transcriptional silencing at TE targets. TE repression by piRNAs is essential for animal fertility, yet its mechanism is not known. Candidate's previous work showed that localization to chromatin of the conserved SUMO E3 ligase Su(var)2- 10 induces heterochromatin formation in germ cells of the Drosophila ovary. Data led to a model that Su(var)2- 10 forms a complex with piRNA-Piwi at genomic targets, and deposits SUMO at yet-to-be-established factor(s), which in turn recruits the H3K9me3 writer dSetDB1. Su(var)2-10 also controls H3K9me3 deposition at piRNA- independent loci, including genes of several silencing factors, indicating a novel negative feedback mechanism between heterochromatin levels and silencing factors that can explain how germ cells maintain heterochromatin levels to ensure proper genome function. This proposal presents a strategy to elucidate the role of Su(var)2-10/SUMO in piRNA-guided silencing, and to investigate the auto-regulation and developmental inheritance of Su(var)2-10 dependent heterochromatin. The candidate will characterize the substrates of SUMO modification by Su(var)2-10 using state-of-the-art proteomics coupled with RNAi (Aim 1), and use biochemical and genetic approaches to investigate the mechanisms that lead to Su(var)2-10 localization and SUMO-dependent dSetDB1 recruitment to genomic targets (Aim 2). In the long term, the candidate will investigate the proposed model of heterochromatin regulation by negative feedback, and study the stability of repressed chromatin states induced by Piwi and Su(var)2-10 across development (Aim 3). Together, this project will provide deep mechanistic insight into heterochromatin formation in germ cells, and address fundamental principles of epigenetic regulation relevant to normal cell function and disease states. Aim 1 and 2 will be initiated during the K99 phase in Dr. Alexei Aravin's lab at Caltech. This environment will provide all necessary research facilities and training to achieve the proposed goals, and to generate reagents and data for future studies, allowing a smooth transition to an independent researcher phase (Aim 3/R00).


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 = $0 )
2026	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Child Health and Human Development Extramural Research	000	5	12/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $231,384 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Child Health and Human Development Extramural Research	000	5	6/16/2023	NON-COMPETING CONTINUATION	$231,384
														Subtotal = $231,384

Issue Date FY: 2022 ( Subtotal = $237,604 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	900 UNIVERSITY AVE	RIVERSIDE	CA	92521	RIVERSIDE	USA	Child Health and Human Development Extramural Research	001	4	6/30/2022	NON-COMPETING CONTINUATION	$231,842
2022	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Child Health and Human Development Extramural Research	000	3	10/27/2021	EXTENSION WITH OR WITHOUT FUNDS	$5,762
														Subtotal = $237,604

Issue Date FY: 2021 ( Subtotal = $248,708 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFFICE BLDG	RIVERSIDE	CA	92521	RIVERSIDE	USA	Child Health and Human Development Extramural Research	000	3	8/27/2021	EXTENSION WITH OR WITHOUT FUNDS	$248,708
														Subtotal = $248,708

Grand Total All Awards = $717,696

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Elucidating the role of SUMO ligase Su(var)2-10 in piRNA-guided transcriptional silencing and repressive chromatin formation

Award Number: R00HD099316

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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