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Understanding the mechanism of Piwi-induced transcriptional silencing

Award Number: R01GM110217
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: 08/01/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Understanding the mechanism of Piwi-induced transcriptional silencing - Project summary The piRNA pathway is an evolutionarily conserved mechanism that acts in the germline of metazoans to repress the activity of transposable elements and ensure genome integrity and fertility. At the core of the pathway lies an Argonaute protein of the Piwi clade and the associated small non-coding RNA, piwi-interacting (pi)RNA, which guides the Piwi protein to its targets. In the cytoplasm Piwi proteins act by destroying the mRNA targets using their intrinsic nuclease activity. piRNA also guide nuclear the Piwi to establish repressive chromatin and induce transcriptional repression of genomic targets. We have found that SUMO and an E3 SUMO ligase play an essential role in piRNA-guided transcriptional repression by linking the nuclear Piwi complex to the chromatin modifier. However, individual steps of piRNA-guided chromatin repression remain poorly understood. In this proposal, we will investigate the molecular mechanism of piRNA-guided repression. We will determine how the SUMO ligase is recruited to genomic piRNA targets and explore the role of SUMO in assembly of the repressive piRNA complexes. We will determine functions of Piwi and piRNA in establishment of repressive chromatin and initiation of piRNA biogenesis. In addition to its function in the germline of adult flies, the maternal Piwi-piRNA complex is deposited into the egg and was proposed to activate piRNA biogenesis in the progeny. However, Piwi is indispensable for oogenesis preventing direct interrogation of its embryonic function. To circumvent this problem and study the function of maternal Piwi in embryogenesis we have developed a strategy for depleting maternal Piwi in the embryo. We will apply this strategy to probe the role of Piwi in specification of piRNA clusters in primordial germ cells. How distinct chromatin domains are demarcated is the central question of chromatin biology. In animals, heterochromatin is disassembled in gametes and re-established during embryogenesis. How heterochromatin is assembled de novo during development remains poorly understood. Transposable elements comprise the bulk of heterochromatin, making Piwi-piRNA complexes an ideal tool for finding and marking heterochromatin sequences. During early zygotic development maternal Piwi-piRNA complexes are localized to somatic nuclei of the embryo. We propose that Piwi-bound piRNAs direct de novo establishment of repressive chromatin domains in somatic cells of the early embryo followed by its piRNA-independent propagation and maintenance during later development. We will explore this model by depleting maternal Piwi and analyzing its effect on chromatin. The proposed work will advance our knowledge of RNA-mediated regulation and of transcription chromatin structure in animals. We explore the function of piRNA in transmission of epigenetic information from generation to generation. Our studies promise to shed new light on how distinct chromatin domains are demarked. A detailed mechanistic understanding of Piwi-induced silencing, which prevents transposon activity and DNA damage in germ cells, will facilitate the development of individualized treatment strategies for human sterility.


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 = -$344,381 )
2026	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	9	12/19/2025	NON-COMPETING CONTINUATION	-$344,381
														Subtotal = -$344,381

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	9	6/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $351,750 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	9	7/30/2024	NON-COMPETING CONTINUATION	$351,750
														Subtotal = $351,750

Issue Date FY: 2023 ( Subtotal = $351,750 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	7/18/2023	NON-COMPETING CONTINUATION	$351,750
														Subtotal = $351,750

Issue Date FY: 2022 ( Subtotal = $351,750 )
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	002	7	7/20/2022	NON-COMPETING CONTINUATION	$351,750
2022	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	001	6	4/3/2022	COMPETING CONTINUATION	$17,933
2022	2019	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	5	4/3/2022	NON-COMPETING CONTINUATION	-$17,933
														Subtotal = $351,750

Issue Date FY: 2021 ( Subtotal = $351,750 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	6	7/28/2021	COMPETING CONTINUATION	$351,750
														Subtotal = $351,750

Issue Date FY: 2019 ( Subtotal = $320,994 )
2019	2019	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	5	7/19/2019	NON-COMPETING CONTINUATION	$320,994
														Subtotal = $320,994

Issue Date FY: 2018 ( Subtotal = $400,994 )
2018	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	001	4	9/19/2018	SUPPLEMENT FOR EXPANSION	$80,000
2018	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	7/9/2018	NON-COMPETING CONTINUATION	$320,994
														Subtotal = $400,994

Issue Date FY: 2017 ( Subtotal = $320,994 )
2017	2017	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	8/2/2017	NON-COMPETING CONTINUATION	$320,994
														Subtotal = $320,994

Issue Date FY: 2016 ( Subtotal = $320,994 )
2016	2016	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	8/24/2016	NON-COMPETING CONTINUATION	$320,994
														Subtotal = $320,994

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2014	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	8/21/2015	NEW	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $320,913 )
2014	2014	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	7/25/2014	NEW	$320,913
														Subtotal = $320,913

Grand Total All Awards = $2,747,508

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Understanding the mechanism of Piwi-induced transcriptional silencing

Award Number: R01GM110217

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: 08/01/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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