# Long Noncoding RNA Control of Cardiac Gene Expression

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $385,000

## Abstract

Abstract
Heart development and pathological remodeling are controlled by a network of transcription factors and non-
coding RNAs that coordinate the expression of genes involved in cardiomyocyte proliferation, morphogenesis,
protein synthesis, and contractility. In response to injury or hemodynamic stress, the adult myocardium
undergoes compensatory hypertrophic growth that is characterized by an increase in cardiomyocyte cell size
and reactivation of fetal cardiac genes. Sustained hypertrophy is a major risk factor for the development of
systolic dysfunction and the progression to clinical heart disease. Identifying novel regulators of cardiac growth
is vital to the development of therapeutics for the treatment of heart disease, which remains a leading cause of
mortality in the United States.
 Serum response factor (SRF) is a widely-expressed transcription factor that regulates the expression of
both muscle-specific and growth factor-inducible genes. In response to extracellular cues, SRF associates with
diverse cell-type and signal-responsive transcriptional coactivators to switch between opposing mitogenic and
myogenic gene programs that balance cardiomyocyte proliferation and differentiation. Myocardin is a potent
coactivator of SRF that is essential for cardiac muscle differentiation and hypertrophy. We recently identified a
novel long noncoding RNA (lncRNA) transcribed upstream of the myocardin locus, that we named the
myocardin-associated long noncoding RNA, or CARDINAL. CARDINAL is significantly upregulated with
myocardin during heart failure in both humans and mice, suggesting it plays an important role in the gene
expression programs required to maintain normal heart function and ventricular remodeling in response to
cardiac injury. In preliminary studies, we found that CARDINAL was robustly activated by myocardin and is a
nuclear lncRNA that associates with chromatin. Genetic disruption of CARDINAL in mice resulted in ectopic
expression of SRF-regulated mitogenic genes and decreased cardiac function. Interestingly, we found that
CARDINAL forms a complex with SRF, suggesting it functions as the first described lncRNA coregulator of
SRF-dependent gene networks in the heart.
 Long noncoding RNAs are an emerging class of transcriptional coregulators that remain largely
unexplored, in part due to the difficulty in determining their binding partners and target genes. In this proposal,
we will determine the role of CARDINAL in directly mediating cardiac gene expression using biochemical, cell-
based, and unique animal models to investigate the molecular and biological significance of CARDINAL in the
heart. We have developed a novel yeast three hybrid approach to identify protein binding partners for lncRNAs,
which we will utilize to identify and characterize components of the CARDINAL-SRF regulatory complex. These
studies will further our knowledge of the basic mechanisms controlling cardiac gene transcription, and will be
broadly useful for ...

## Key facts

- **NIH application ID:** 10138015
- **Project number:** 5R01HL151583-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Douglas Matthew Anderson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2020-04-03 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138015

## Citation

> US National Institutes of Health, RePORTER application 10138015, Long Noncoding RNA Control of Cardiac Gene Expression (5R01HL151583-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10138015. Licensed CC0.

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