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Role of Negative Elongation Factor Complex in RNA polymerase II pausing and gene transcription in Heart

Award Number: R01HL150059
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Role of Negative Elongation Factor Complex in RNA polymerase II pausing and gene transcription in Heart - PROJECT SUMMARY/ABSTRACT Congestive heart failure is one of the leading cause of morbidity and mortality in the USA and the World. However, despite the major advancements in research and therapeutic developments, there has been no improvement in death rates over the years. This necessitates reinvestigating the basic mechanisms that govern the progression heart failure. Adaptation of gene expression is the earliest fundamental response during overload. We have shown the widespread regulatory influence of promoter-proximal RNA polymerase II (pol II) pausing on gene transcription in heart. However, the underlying mechanisms that control and synchronize the release of paused pol II for active transcription are unclear and conflicting, and its contribution to development of cardiac hypertrophy and failure still unknown. Negative elongation factors (Nelf), comprising of five subunits (NelfA to NelfE) has been implicated in pol II pausing, with NelfA subunit identified as an essential component for pausing. Our preliminary data shows increase in NelfA expression with cardiac hypertrophy, which is required for compensatory increase in gene expression in these hearts. Conversely, NelfA levels decline in failing hearts, suggesting downregulation of NelfA could be contributing to decompensation and progression of failure. Our genome-wide sequencing data shows widespread NelfA occupancy on active promoters including inducible and constitutively expressed essential genes. Interestingly, immunoprecipitation of chromatin bound NelfA shows association with chromatin remodelers and pre-mRNA processing proteins. In this study, we investigate the role of NelfA in pol II dynamics, chromatin remodeling and gene expression, and its impact on progression of heart failure. We have hypothesized that adaptation of gene expression during cardiac hypertrophy is achieved by phosphorylation dependent increase in the rate of clearance of paused pol II from essential gene promoters, and de novo recruitment of NelfA and assembly of paused complex at inducible promoters. Loss of NelfA results in disrupted paused complex, altered chromatin remodeling, inefficient transcript processing and inhibited gene expression that precipitates heart failure. We have proposed two robust specific aims to test our hypothesis – 1. To examine the mechanisms regulating NelfA -dependent pol II pausing in gene transcription during cardiac hypertrophy. 2. To investigate the effects of loss of NelfA on gene expression and progression of heart failure in conditional NelfA-KO model subjected to pressure overload.


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: 2026 ( Subtotal = $0 )
2026	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	000	5	10/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $583,773 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	000	5	1/28/2025	NON-COMPETING CONTINUATION	$525,396
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	001	5	8/29/2025	NON-COMPETING CONTINUATION	$58,377
														Subtotal = $583,773

Issue Date FY: 2024 ( Subtotal = $572,097 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	000	4	12/28/2023	NON-COMPETING CONTINUATION	$525,396
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	003	4	6/12/2024	NON-COMPETING CONTINUATION	$46,701
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	002	3	4/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$365,683
2024	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	2	4/5/2024	NON-COMPETING CONTINUATION	-$365,683
														Subtotal = $572,097

Issue Date FY: 2023 ( Subtotal = $583,773 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	001	3	12/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$525,396
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cardiovascular Diseases Research	002	3	3/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$58,377
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	2	12/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $583,773

Issue Date FY: 2022 ( Subtotal = $583,773 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	2	12/27/2021	NON-COMPETING CONTINUATION	$525,395
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	2	5/31/2022	NON-COMPETING CONTINUATION	$58,378
														Subtotal = $583,773

Issue Date FY: 2021 ( Subtotal = $560,905 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	001	1	7/28/2021	NEW	$37,183
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Cardiovascular Diseases Research	000	1	2/15/2021	NEW	$523,722
														Subtotal = $560,905

Grand Total All Awards = $2,884,321

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Role of Negative Elongation Factor Complex in RNA polymerase II pausing and gene transcription in Heart

Award Number: R01HL150059

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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