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Computational and Experimental Modeling of Alternative Polyadenylation

Award Number: R01CA193466
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2015
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Computational and Experimental Modeling of Alternative Polyadenylation - Project Summary / Abstract Alternative polyadenylation (APA) plays an important role in the post-transcriptional regulation of most human genes. The broad importance of APA is well exemplified by the altered expression of NUDT21, a key APA regulator that we reported in the first cycle of this grant, in diseases such as glioblastoma, diopathic pulmonary fibrosis, and neuropsychiatric disorders. More recently, our work has revealed a novel mechanism by which 3ʹ- UTR shortening can repress tumor suppressor genes (e.g., PTEN) in trans by disrupting competing endogenous RNA (ceRNA) crosstalk, rather than by inducing oncogenes in cis. Aside from these few examples, the prevalence and functions of APA in a wide spectrum of human traits and diseases remain largely unknown. Most human traits/diseases have been found as associated with hundreds of thousands of noncoding single-nucleotide polymorphisms (SNPs) in numerous genome-wide association studies (GWASs). However, functional interpretation of these SNPs remains a significant challenge because GWAS data do not show how the SNPs work. To better understand their effects, expression quantitative trait loci (eQTLs) have been widely used to link GWAS SNPs to gene expression. Despite massive efforts on elucidating eQTLs, the functions of many GWAS SNPs remain unexplained. An important reason is that eQTLs do not consider APA regulation. We have recently constructed the first human 3′UTR APA quantitative trait loci (3′aQTLs), which contain ~0.4 million SNPs associated with APA of target genes, using ~8,000 GTEx v7 RNA-seq samples across 46 tissue types (Nature Genetics, accepted in 2021). These 3′aQTLs can explain ~16.1% of GWAS SNPs in 15 common traits/diseases, and they are largely distinct from eQTLs and splicing QTLs. Based on these exciting preliminary data, we hypothesize that computational and experimental modeling of APA will substantially facilitate the interpretation of numerous GWAS SNPs important for APA regulation, which are enriched in 3′UTRs and gene downstream regions. Hence, we propose to develop innovative bioinformatics and experimental methods for identifying 3′aQTLs and nominating APA-linked disease/trait susceptibility genes in a wide variety of cell types and environmental factors, followed by in vivo functional characterization using our unique CRISPR engineering system. We expect to establish APA as an emerging and important molecular phenotype to explain a large fraction of GWAS risk SNPs, leading to significant novel biological insights into the genetic basis of APA and APA-linked susceptibility genes in a wide spectrum of human traits and diseases.


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 = $360,307 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	10	2/14/2025	NON-COMPETING CONTINUATION	$324,276
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	001	10	5/22/2025	NON-COMPETING CONTINUATION	$36,031
														Subtotal = $360,307

Issue Date FY: 2024 ( Subtotal = $342,290 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	9	1/30/2024	NON-COMPETING CONTINUATION	$324,275
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	001	9	4/23/2024	NON-COMPETING CONTINUATION	$18,015
														Subtotal = $342,290

Issue Date FY: 2023 ( Subtotal = $353,100 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	8	3/6/2023	NON-COMPETING CONTINUATION	$353,100
														Subtotal = $353,100

Issue Date FY: 2022 ( Subtotal = $388,808 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	002	7	4/7/2022	COMPETING CONTINUATION	$416,566
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	000	7	3/21/2022	COMPETING CONTINUATION	$388,808
2022	2020	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	001	6	4/7/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$416,566
														Subtotal = $388,808

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	000	6	1/13/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $362,569 )
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	5	1/13/2020	NON-COMPETING CONTINUATION	$36,257
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	11/6/2019	NON-COMPETING CONTINUATION	$326,312
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	006	6	9/16/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$325,969
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	005	5	9/16/2020	NON-COMPETING CONTINUATION	-$40,546
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	003	6	4/29/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$322,023
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	5	4/29/2020	NON-COMPETING CONTINUATION	-$322,023
2020	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	004	4	9/16/2020	NON-COMPETING CONTINUATION	-$285,423
														Subtotal = $362,569

Issue Date FY: 2019 ( Subtotal = $351,691 )
2019	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	11/19/2018	NON-COMPETING CONTINUATION	$351,691
														Subtotal = $351,691

Issue Date FY: 2018 ( Subtotal = $361,128 )
2018	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	3	5/22/2018	NON-COMPETING CONTINUATION	$36,114
2018	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	11/27/2017	NON-COMPETING CONTINUATION	$325,014
														Subtotal = $361,128

Issue Date FY: 2017 ( Subtotal = $361,128 )
2017	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	2	6/7/2017	NON-COMPETING CONTINUATION	$36,114
2017	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	11/24/2016	NON-COMPETING CONTINUATION	$325,014
														Subtotal = $361,128

Issue Date FY: 2016 ( Subtotal = $374,510 )
2016	2016	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	11/23/2015	NEW	$374,510
														Subtotal = $374,510

Grand Total All Awards = $3,255,531

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Computational and Experimental Modeling of Alternative Polyadenylation

Award Number: R01CA193466

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2015

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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