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Investigating the effects of structural variants on 3D genome organization and gene regulation in cancer genomes

Award Number: U01CA260700
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Three-dimensional genome organization has emerged as a critical component for the proper regulation of gene expression. Recent years have seen a rapid expansion of the understanding of many of the basic features that define how genomes are organized in space inside of cells, including the identification of features such as A/B compartments, Topologically Associated Domains, and chromatin loops. Furthermore, there is evidence that mutations that alter 3D genome organization can contribute to human disease. This is most evident for a class of mutations known as structural variants, which includes translocations, inversions, tandem duplications, and deletions. When these mutations disrupt sequence features that are critical for 3D genome structure, such as the boundaries between Topologically Associating Domains, this can lead to enhancer-promoter rewiring, changes in gene expression, and phenotypic consequences. Such effects have been observed both in the context of germline structural variants that contribute to syndromic disorders of development as well as somatic structural variants that can lead to cancer. While it has become clear that structural variants can alter 3D genome organization and gene expression, more recent studies that comprehensively examined structural variants and gene expression indicate their relationship is considerably more complex. Specifically, in only a minority of instances do structural variants lead to changes in expression of neighboring genes. Therefore, why structural variants can have dramatic consequences on 3D genome structure and gene expression in some contexts but not others is currently unclear. This proposal will investigate the relationship between structural variants, 3D genome organization, and gene expression in cancer genomes with the goal of understanding where and when structural variants will actually lead to changes in gene expression that may contribute to oncogenesis. Specific aim 1 will test whether only specific sets genes are sensitive to structural variant induced changes in enhancer-promoter communication by examining changes in 3D genome structure and gene expression in haplotype resolved human tumor samples. Specific aim 2 will use CRISPR/Cas9 genome engineering to evaluate the effects of structural variant partner regions on induction of oncogene expression. Specific aim 3 will assess the role of intra-tumor heterogeneity on the effects of structural variants on 3D genome structure by using novel multi-omic methods for profiling DNA methylation and 3D genome structure simultaneously within single cells derived from patient tumor samples. Successful completion of these aims will result in a deeper understanding of the relationship between structural variation, 3D genome organization, and gene regulation in the context of cancer genomes. In the long term, this will facilitate the use of information derived from structural variants and 3D genome structure on determining patient prognosis and on identifying novel therapeutic targets in cancer.


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: 2023 ( Subtotal = $693,955 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Research Support	000	4	8/10/2023	NON-COMPETING CONTINUATION	$693,955
														Subtotal = $693,955

Issue Date FY: 2022 ( Subtotal = $693,955 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Research Support	001	3	8/26/2022	NON-COMPETING CONTINUATION	$693,955
2022	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Research Support	000	2	3/11/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $693,955

Issue Date FY: 2021 ( Subtotal = $693,955 )
2021	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Research Support	000	2	8/5/2021	NON-COMPETING CONTINUATION	$693,955
														Subtotal = $693,955

Issue Date FY: 2020 ( Subtotal = $693,955 )
2020	2020	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Research Support	000	1	9/15/2020	NEW	$693,955
														Subtotal = $693,955

Grand Total All Awards = $2,775,820

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Investigating the effects of structural variants on 3D genome organization and gene regulation in cancer genomes

Award Number: U01CA260700

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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