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Cross-regulation between transcription and pre-mRNA splicing

Award Number: R01GM112766
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: 09/01/2015
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Cross-regulation between transcription and pre-mRNA splicing - Abstract/Project Summary The ubiquitous need for transcription and pre-mRNA processing in eukaryotes requires an understanding of the mechanisms by which they occur simultaneously and regulate each other. Our long-term goals are to determine the mechanisms that govern co-transcriptional intron removal and how co-transcriptional splicing contributes to gene expression regulation. With previous support from this grant, my lab has pioneered strategies for purifying and sequencing nascent RNA – the transient intermediates in transcription and RNA processing – to quantify pre-mRNA splicing relative to the position of elongating RNA Polymerase II (Pol II) on the gene. Most introns are removed as soon as they emerge from Pol II, indicating that Pol II and the spliceosome are timed to act together and physically close to one another. Knowing this, our overall objectives are to (i) elucidate the co-transcriptional mechanism of “all-or-none” RNA processing, in which individual nascent transcripts are either fully spliced and cleaved at the 3’ end (all) or fully unspliced and uncleaved (none). My lab discovered this recently by sequencing full-length nascent RNAs, and it is a major co-transcriptional regulatory mechanism for b-globin gene expression. (ii) Determine how the potential for splicing becomes limited as transcription proceeds and the nascent transcript gets longer. And (iii) Determine the fate and possible function of the unprocessed transcripts. The central hypothesis is that the potential for nascent RNA to bind positive- and negative-acting RNA binding proteins and/or to undergo intermolecular base-pairing and compaction increases as the nascent chain grows during transcription. We will test this hypothesis by pursuing three specific aims: 1) develop a method to determine the local base-pairing behavior of nascent RNA, using DMS chemistry and nascent RNA purification. The results of this aim will tell us the degree to which nascent RNA becomes transiently structured during transcription and if local structures correlate with positive or negative effects on splicing, 2) identify activator and/or repressor proteins that accumulate on the growing nascent chain during transcription, using biochemical purification and in vivo labeling approaches. 3) determine the nuclear response to unprocessed “none” transcripts. Are they delayed in processing? Or will they be degraded? For this aim, we have established the A-count method, which sequences the entire transcript from 5’ end to 3’ end, including the whole length of the polyA tail, which will be counted by nucleotide type and number. Our preliminary results show that the nuclear polyA binding protein PABPN1 is regulated by phosphorylation during mitosis, suggesting differential fates for nuclear retained mRNAs with introns. PABPN1 is a protein mutated in Oculopharyngeal muscular dystrophy (OPMD). The proposed research is significant because these mechanisms operating at the level of pre-mRNA processing can change protein product amounts by at least 10-fold, showing that RNA processing is as important for gene expression as regulation by transcription factors.


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 = $458,364 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	11	5/19/2025	NON-COMPETING CONTINUATION	$458,364
														Subtotal = $458,364

Issue Date FY: 2024 ( Subtotal = $461,561 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	002	10	5/8/2024	NON-COMPETING CONTINUATION	$461,561
2024	2023	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	9	4/17/2024	COMPETING CONTINUATION	$770
2024	2022	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	8	4/17/2024	NON-COMPETING CONTINUATION	-$770
														Subtotal = $461,561

Issue Date FY: 2023 ( Subtotal = $504,132 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	9	8/18/2023	COMPETING CONTINUATION	$504,132
2023	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	8	8/9/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $504,132

Issue Date FY: 2022 ( Subtotal = $434,691 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	8	5/13/2022	NON-COMPETING CONTINUATION	$434,691
														Subtotal = $434,691

Issue Date FY: 2021 ( Subtotal = $434,691 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	7	5/18/2021	NON-COMPETING CONTINUATION	$434,691
														Subtotal = $434,691

Issue Date FY: 2020 ( Subtotal = $434,742 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	6	5/22/2020	NON-COMPETING CONTINUATION	$434,742
2020	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	4	2/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $434,742

Issue Date FY: 2019 ( Subtotal = $456,817 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	4	5/20/2019	SUPPLEMENT FOR EXPANSION	$16,200
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	001	5	5/29/2019	COMPETING CONTINUATION	$440,617
														Subtotal = $456,817

Issue Date FY: 2018 ( Subtotal = $417,230 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	4	5/28/2018	NON-COMPETING CONTINUATION	$417,230
														Subtotal = $417,230

Issue Date FY: 2017 ( Subtotal = $432,561 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	3	5/26/2017	NON-COMPETING CONTINUATION	$432,561
														Subtotal = $432,561

Issue Date FY: 2016 ( Subtotal = $385,995 )
2016	2016	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	2	5/25/2016	NON-COMPETING CONTINUATION	$385,995
														Subtotal = $385,995

Issue Date FY: 2015 ( Subtotal = $385,995 )
2015	2015	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Biomedical Research and Research Training	000	1	8/27/2015	NEW	$385,995
														Subtotal = $385,995

Grand Total All Awards = $4,806,779

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Cross-regulation between transcription and pre-mRNA splicing

Award Number: R01GM112766

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: 09/01/2015

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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