# Transcription cycle regulation by nutrients

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $336,600

## Abstract

PROJECT SUMMARY
 Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with an estimated
global prevalence of 1 in 4 individuals. No FDA-approved treatments are available. Aberrant transcriptional
control of gene expression is central to the pathophysiology of metabolic diseases. Transcription by RNA
Polymerase II (RNAP2) occurs through several coordinated steps, which include pre-initiation complex
formation and initiation, elongation, and termination. The assembly of the basal transcription machinery and
transcription initiation was believed for many years to be the rate-limiting and most important aspect driving
gene expression. Recent research has revealed that the transition from initiation to elongation is a rate-limiting
and critical step, requiring specific signals to release RNAP2 from its paused state and engage in transcription
elongation. RNAP2 pause-release is a mechanism that allows fast and synchronized gene expression in
response to environmental cues, adjusting expression of entire gene programs. The process of pause-release
requires histone H3 acetylation at lys9 (H3K9ac) in the promoter-proximal region. H3K9ac levels are
significantly altered by high-fat feeding in mice, a model of diet-induced obesity, insulin resistance and NAFLD.
We hypothesize that RNAP2 pause-release is a fundamental mechanism of gene regulation in response to
nutrient availability, and under conditions of nutrient excess, misregulated pause-release contributes to
aberrant changes in gene expression. To study how cells respond to nutrients at the genome-wide level, high-
throughput sequencing technologies will be used. The goals of this proposal will be achieved by pursuing the
following specific aims: (i) Define the role of RNAP2 pause-release in transcription regulation in the fasted to
refed transition; (ii) Determine the mechanism by which the pro-lipogenesis transcription factor Sterol
Regulatory Element Binding Protein 1 (SREBP-1) contributes to regulate transcription elongation; (iii)
Determine how H3K9ac contributes to change gene expression under high-fat conditions. This proposal is
significant because it will identify a novel node of transcription regulation, breaking new ground for drug target
discovery. Thus, this proposal addresses a basic scientific gap in the field of metabolism, and the results of
these innovative studies could lead to the development of new and effective therapeutic interventions for
NAFLD, type 2 diabetes and other associated metabolic diseases.

## Key facts

- **NIH application ID:** 10820451
- **Project number:** 5R01DK131143-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** NURIA MORRAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $336,600
- **Award type:** 5
- **Project period:** 2022-07-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820451

## Citation

> US National Institutes of Health, RePORTER application 10820451, Transcription cycle regulation by nutrients (5R01DK131143-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10820451. Licensed CC0.

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