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

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2021 · $560,905

## Abstract

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.

## Key facts

- **NIH application ID:** 10120220
- **Project number:** 1R01HL150059-01A1
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Danish Sayed
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $560,905
- **Award type:** 1
- **Project period:** 2021-02-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120220

## Citation

> US National Institutes of Health, RePORTER application 10120220, Role of Negative Elongation Factor Complex in RNA polymerase II pausing and gene transcription in Heart (1R01HL150059-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10120220. Licensed CC0.

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