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Genomics-based approaches to understanding mechanistic alterations of spliceosome function in disease states

Award Number: R01GM141544
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: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Genomics-based approaches to understanding mechanistic alterations of spliceosome function in disease states - Splicing factors are frequently altered by mutations and copy-number changes both in cancer and in germline genetic diseases resulting in multi-system developmental syndromes. Despite the fact that virtually all genes in humans undergo splicing, spliceosomal genetic alterations tend to exhibit surprisingly specific effects on subsets of splicing events, leaving most insignificantly changed. These effects can be allele-specific, cell-type specific, and dependent on the genetic background of the afflicted cell. This makes it especially challenging to determine which affected splicing events contribute to disease etiology. The fact that a limited set of introns is responsive to any specific splicing factor alteration indicates that introns and their flanking exons have evolved in structure and sequence to confer differential sensitivity to the action of different spliceosome components. This raises a fundamental question: what are the features common to sets of introns that confer this specificity? Using naturally occurring splicing gene mutations, amplifications, and deletions, these perturbations will be modelled in a genetically stable, untransformed, isogenic cell system where it is possible to isolate the effect of a single alteration on the transcriptome and on the binding patterns of the altered protein. These studies will shed light on the mechanisms of normal spliceosome function, and provide insight into which genes and biological pathways affected by splicing dysfunction likely contribute to disease states. The proposed experiments will employ three distinct methods to model spliceosome perturbations associated with human disease, with a focus on factors that physically or functionally interact with the essential spliceosome protein SF3B1. (Specific Aim 1) Introduction of an allelic series of cancer-associated SF3B1 missense-mutations into isogenic cell lines using recombinase-mediated cassette exchange (RMCE); (Specific Aim 2) CRISPRa/i-mediated activation or inhibition of transcription to up- or down- regulate splicing factors that are amplified in cancers (PUF60, SF3B4, and U2AF2) and lost in developmental syndromes (PUF60, SF3B4); and (Specific Aim 3) rapid depletion of spliceosomal RNA helicases (DDX39B, DDX46, and DHX16) and their putative co-factors (SUGP1, RBM17, and GPKOW) at the protein level using auxin-inducible degrons. Three distinct methods of RNA sequencing will be used to quantify the changes resulting from these perturbations: poly(A)-selected RNAseq, allele-specific eCLIP, and a novel intron lariat capture sequencing approach. Lastly, we will integrate these genomic data sets into models using deep learning neural networks to interrogate our central hypothesis: the sequence and structure of individual mammalian introns have evolved to confer differential dependence on specific ‘core’ components of the spliceosome, and that mutations, amplifications, and deletions in these core components causal for human disease will uncover intron-centric gene expression regulatory circuits that are controlled though modulation of the abundance or activity of the associated splicing factors in normal cells.


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 = $323,400 )
2025	2025	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Biomedical Research and Research Training	000	5	1/24/2025	NON-COMPETING CONTINUATION	$291,060
2025	2025	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Biomedical Research and Research Training	001	5	8/13/2025	NON-COMPETING CONTINUATION	$32,340
														Subtotal = $323,400

Issue Date FY: 2024 ( Subtotal = $323,400 )
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Biomedical Research and Research Training	000	4	1/10/2024	NON-COMPETING CONTINUATION	$291,060
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Biomedical Research and Research Training	001	4	7/10/2024	NON-COMPETING CONTINUATION	$32,340
														Subtotal = $323,400

Issue Date FY: 2023 ( Subtotal = $323,400 )
2023	2023	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Biomedical Research and Research Training	001	3	3/28/2023	NON-COMPETING CONTINUATION	$32,340
2023	2023	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Biomedical Research and Research Training	000	3	1/10/2023	NON-COMPETING CONTINUATION	$291,060
														Subtotal = $323,400

Issue Date FY: 2022 ( Subtotal = $323,400 )
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Biomedical Research and Research Training	000	2	1/12/2022	NON-COMPETING CONTINUATION	$291,060
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Biomedical Research and Research Training	001	2	6/23/2022	NON-COMPETING CONTINUATION	$32,340
														Subtotal = $323,400

Issue Date FY: 2021 ( Subtotal = $323,400 )
2021	2021	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Biomedical Research and Research Training	000	1	2/26/2021	NEW	$323,400
														Subtotal = $323,400

Grand Total All Awards = $1,617,000

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Genomics-based approaches to understanding mechanistic alterations of spliceosome function in disease states

Award Number: R01GM141544

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: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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