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Single Cell Tracking of 3D Epigenetic Landscape Evolution During Embryonic Development

Award Number: R01HD107206
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: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Single Cell Tracking of 3D Epigenetic Landscape Evolution During Embryonic Development - Single Cell Tracking of 3D Epigenetic Landscape Evolution During Embryonic Development An important question to cell biology is how cells break the symmetry during mitotic divisions. During mammalian pre-implantation embryonic development (PED), how the first cell fate decision is made remains unclear and is crucial for the understanding of how specific gene regulations can guide the life of a cell. Epigenetic modifications including chromatin remodeling are early events during PED. Histone methylation at different residues can recruit differential sets of chromatin remodeling complexes to regulate chromatin structures and silence/activate gene expressions accordingly. These histone methylations and their combinations at different genomic loci can serve as codes to determine the overall gene expression profile and phenotypic outcomes. However, it is still not understood how histone methylations and hence chromatin structures at specific loci are dynamically regulated during PED in which cells undergo a heterogeneous modulation at single cell levels. In this proposal, we will harness the power of directed evolution and high-throughput screening method to systematically develop specific/sensitive FRET (fluorescence resonance energy transfer) biosensors for the monitoring of crucial histone methylations in single cells. We will further develop and apply the mapping RNA-chromatin interactions in single cells (sciMARGI) to identify crucial RNA-genome interaction sites during PED. We will then employ the endonuclease-deficient Cas9 (dCas9), small guide RNAs (sgRNAs) and split FPs to identify and track the positons of specific loci crucial for embryonic cell differentiation. Ultimately, we will apply our controllable epigenetic modulators to guide the histone modulations at specific loci and elucidate their role in determining cell fates during PED. Given the importance of epigenetic modifications at different loci, the success of the project should have transformative impact in understanding the role of locus-specific epigenetics in determining the cell fate during PED. Accordingly, three aims are proposed: Aim 1. Spatiotemporal imaging of crucial histone methylations in single live cells and during PED; Aim 2. Visualize the locus-specific histone modifications during PED; Aim 3. Reprogram the locus-specific histone modifications during PED. While the focus of this proposal is to develop tools targeting histone methylations and chromatin structures at specific loci and differentiation outcomes, the strategies and approaches can be extended to monitor, in principle, any other epigenetic modification in single cells, including but not limited to histone acetylation and phosphorylation. The results from this project can also lead directly to the dynamic nuclear atlas illustrating how specific histone codes are encrypted in an integrative manner for the regulation of life.


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 = $610,686 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	000	5	2/26/2026	NON-COMPETING CONTINUATION	$610,686
														Subtotal = $610,686

Issue Date FY: 2025 ( Subtotal = $622,593 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	001	4	4/11/2025	NON-COMPETING CONTINUATION	$62,260
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	002	4	7/17/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	000	4	3/10/2025	NON-COMPETING CONTINUATION	$560,333
														Subtotal = $622,593

Issue Date FY: 2024 ( Subtotal = $630,203 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	001	3	4/30/2024	NON-COMPETING CONTINUATION	$57,292
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	000	3	2/27/2024	NON-COMPETING CONTINUATION	$572,911
														Subtotal = $630,203

Issue Date FY: 2023 ( Subtotal = $652,393 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	000	2	3/20/2023	NON-COMPETING CONTINUATION	$652,393
														Subtotal = $652,393

Issue Date FY: 2022 ( Subtotal = $679,397 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Child Health and Human Development Extramural Research	000	1	3/1/2022	NEW	$679,397
														Subtotal = $679,397

Grand Total All Awards = $3,195,272

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Single Cell Tracking of 3D Epigenetic Landscape Evolution During Embryonic Development

Award Number: R01HD107206

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: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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