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The impact of genomic variation on environment-induced changes in pancreatic beta cell states

Award Number: U01HG012059
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/07/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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The impact of genomic variation on environment-induced changes in pancreatic beta cell states - PROJECT SUMMARY/ABSTRACT Pancreatic beta cells secrete insulin in order to maintain blood glucose homeostasis. Insulin secretion is tightly regulated by glucose and modulated by numerous environmental signals, including other nutrients, hormones, and inflammatory cytokines. Exposure of beta cells to environmental signals affects gene regulatory programs within hours, and these signal-dependent changes serve to adapt insulin secretion to changes in organismal states. Genetic variants associated with measures of insulin secretion are strongly enriched in genomic elements active in beta cells, and many of these variants are also associated with risk of diabetes. Beta cells therefore possess characteristics that make them an ideal cellular model for studying signal-dependent gene regulatory processes relevant to human health and disease. However, the specific genomic programs that drive signal- induced state changes in beta cells remain poorly characterized. Recent advances in the development of human pluripotent stem cell (hPSC)-derived multi-cellular islet organoid models by us and others provide a genetically tractable beta cell model for linking genomic activity to cellular phenotypes. Our group has further pioneered the development of numerous single cell assays, including chromatin accessibility, ultra-high-throughput paired chromatin accessibility and gene expression, and paired 3D chromatin interactions and DNA methylation; methods that we have successfully applied to both primary human islets and hPSC-islet organoids. We have further developed machine learning and network-based approaches for variant interpretation including from single cell RNA and epigenetic data. In this proposal we will develop novel gene regulatory network (GRN) models to predict network-level relationships among genomic elements, genes, and phenotypes derived from single cell multiomic maps charting signal- and time-dependent changes in hPSC-islet organoids. In Sections B and C we will measure genomic element activity, gene expression, and insulin secretion in hPSC-islet organoids exposed to ten different secretory signals each across four time points using paired single nucleus accessible chromatin and gene expression and paired single cell DNA methylation and 3D chromatin architecture assays. In Section D we will generate a GRN from these data, use machine learning to infer element-gene and element-phenotype relationships and use the trained models to refine the GRN. From the resulting GRN we will predict the effects of genetic variants in specific genomic elements on target gene expression, gene network activity, and cellular phenotype. In Section E we will validate and refine models by using medium-scale CRISPR interference of genomic elements individually and in combination as well as allele-specific gene editing of selected glucose-associated variants in hPSC-islet organoids and measuring gene expression changes in cis and trans. Together, the results, data, and methods from this project using a model of a cell type which both rapidly responds to environmental signals and has a quantifiable phenotypic output will be widely applicable to the community studying the dynamics of genomic regulation.


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: 2025 ( Subtotal = $1,254,397 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Human Genome Research	000	5	7/28/2025	NON-COMPETING CONTINUATION	$1,254,397
														Subtotal = $1,254,397

Issue Date FY: 2024 ( Subtotal = $1,254,398 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Human Genome Research	000	4	7/22/2024	NON-COMPETING CONTINUATION	$1,254,398
														Subtotal = $1,254,398

Issue Date FY: 2023 ( Subtotal = $1,280,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Human Genome Research	001	3	7/3/2023	NON-COMPETING CONTINUATION	$1,280,000
2023	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Human Genome Research	000	2	12/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,280,000

Issue Date FY: 2022 ( Subtotal = $1,280,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Human Genome Research	000	2	6/9/2022	NON-COMPETING CONTINUATION	$1,280,000
														Subtotal = $1,280,000

Issue Date FY: 2021 ( Subtotal = $1,280,000 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Human Genome Research	000	1	9/7/2021	NEW	$1,280,000
														Subtotal = $1,280,000

Grand Total All Awards = $6,348,795

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The impact of genomic variation on environment-induced changes in pancreatic beta cell states

Award Number: U01HG012059

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/07/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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