Thursday, April 25, 2024 4/25/2024

Regulation and Function of Alternative mRNA Isoform Expression in Mammals

Award Number: R01HG002439
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Summary Most human genes contain introns, and presence of introns often increases the expression of the host gene, a phenomenon known as intron-mediated enhancement (IME). IME has been observed in diverse genes in animals, plants and fungi and often varies in magnitude across introns. However, little is known about how introns impact expression or what intron features modulate IME activity. Recently, we have described a novel phenomenon that we call exon-mediated activation of transcription starts (EMATS), in which the splicing of internal exons impacts the spectrum of promoters used and expression level of the gene. EMATS acts at a distance of up to a few kb, can alter gene expression by at least severalfold, and appears more active at certain promoters – especially intrinsically weak promoters. The detailed sequence requirements and mode of action of EMATS are not yet known. This proposal is seeks to understand the rules that govern IME and EMATS, to improve the prediction of gene expression and to enable methods to modulate gene expression by altering splicing. It is organized around the following aims. SA1. Determine the sequence dependence of intron-mediated enhancement. SA2. Explore the scope and rules for EMATS regulation. In Aim 1, we will generate a library of many thousands of distinct random sequences inserted into an intron in a dual fluorescent reporter system that is chromosomally integrated into human cells. This design will enable high-throughput measurement of the effects of each intron on nascent RNA, mature RNA and protein levels, and these data will be used to identify motifs that enhance or silence expression in a splicing-dependent manner from an intronic location. In aim 2, we will systematically derive and test rules for how EMATS regulation depends on the location and sequence of the internal exon and on properties of the involved promoter. Finally, we will use the information learned about IME and EMATS to improve predictions of gene expression from primary sequence. Together, the research described in these aims will establish rules governing how splicing impacts gene expression in mammalian genomes. Identification of motifs that function as splicing-dependent activators or silencers of expression can be used to improve prediction of expression from genome sequence and may enable detection of intronic variants that alter expression. Understanding how splicing impacts expression may also enable new approaches for gene expression modulation.


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: 2024 ( Subtotal = $485,089 )
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	20	1/4/2024	NON-COMPETING CONTINUATION	$485,089
														Subtotal = $485,089

Issue Date FY: 2023 ( Subtotal = $528,717 )
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	19	1/6/2023	NON-COMPETING CONTINUATION	$475,848
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	001	19	3/7/2023	NON-COMPETING CONTINUATION	$52,869
														Subtotal = $528,717

Issue Date FY: 2022 ( Subtotal = $518,746 )
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	001	18	5/2/2022	NON-COMPETING CONTINUATION	$51,875
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	18	12/13/2021	NON-COMPETING CONTINUATION	$466,871
														Subtotal = $518,746

Issue Date FY: 2021 ( Subtotal = $509,066 )
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	004	17	5/26/2021	COMPETING CONTINUATION	$1,184
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	002	17	2/9/2021	COMPETING CONTINUATION	$50,907
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	001	17	12/31/2020	COMPETING CONTINUATION	$458,159
2021	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	16	12/30/2020	NON-COMPETING CONTINUATION	$0
2021	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	003	16	5/26/2021	NON-COMPETING CONTINUATION	-$1,184
														Subtotal = $509,066

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	16	6/26/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $489,006 )
2018	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	16	6/1/2018	NON-COMPETING CONTINUATION	$489,006
														Subtotal = $489,006

Issue Date FY: 2017 ( Subtotal = $489,006 )
2017	2017	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	15	5/26/2017	NON-COMPETING CONTINUATION	$489,006
														Subtotal = $489,006

Issue Date FY: 2016 ( Subtotal = $489,006 )
2016	2016	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	14	5/12/2016	COMPETING CONTINUATION	$489,006
														Subtotal = $489,006

Issue Date FY: 2014 ( Subtotal = $490,002 )
2014	2014	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	13	5/28/2014	NON-COMPETING CONTINUATION	$490,002
														Subtotal = $490,002

Issue Date FY: 2013 ( Subtotal = $477,500 )
2013	2013	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	12	6/6/2013	NON-COMPETING CONTINUATION	$477,500
														Subtotal = $477,500

Issue Date FY: 2012 ( Subtotal = $500,001 )
2012	2012	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	001	11	5/24/2012	NON-COMPETING CONTINUATION	$500,001
2012	2010	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	000	9	4/11/2012	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $500,001

Issue Date FY: 2011 ( Subtotal = $573,238 )
2011	2011	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	001	10	8/31/2011	COMPETING CONTINUATION	$573,238
2011	2010	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	9	8/29/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $573,238

Issue Date FY: 2010 ( Subtotal = $903,195 )
2010	2010	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	001	9	3/15/2010	NON-COMPETING CONTINUATION	$404,089
2010	2010	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	002	9	8/12/2010	SUPPLEMENT FOR EXPANSION	$499,106
2010	2009	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	000	8	3/15/2010	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $903,195

Issue Date FY: 2009 ( Subtotal = $734,398 )
2009	2009	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	001	8	4/13/2009	NON-COMPETING CONTINUATION	$39,839
2009	2009	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	8	2/9/2009	NON-COMPETING CONTINUATION	$358,559
2009	2009	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	002	8	9/30/2009	SUPPLEMENT FOR EXPANSION	$336,000
														Subtotal = $734,398

Issue Date FY: 2008 ( Subtotal = $388,909 )
2008	2008	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	7	2/28/2008	NON-COMPETING CONTINUATION	$388,909
														Subtotal = $388,909

Issue Date FY: 2007 ( Subtotal = $412,000 )
2007	2007	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	6	5/9/2007	COMPETING CONTINUATION	$412,000
														Subtotal = $412,000

Issue Date FY: 2006 ( Subtotal = $316,825 )
2006	2006	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	5	2/21/2006	NON-COMPETING CONTINUATION	$316,825
														Subtotal = $316,825

Issue Date FY: 2005 ( Subtotal = $324,450 )
2005	2005	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	4	1/31/2005	NON-COMPETING CONTINUATION	$324,450
														Subtotal = $324,450

Issue Date FY: 2004 ( Subtotal = $324,450 )
2004	2004	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Human Genome Research	000	3	1/30/2004	NON-COMPETING CONTINUATION	$324,450
														Subtotal = $324,450

Grand Total All Awards = $9,659,054

Page 1 of 2 (54 items)12

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Regulation and Function of Alternative mRNA Isoform Expression in Mammals

Award Number: R01HG002439

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer