# Transcriptional Control of Myocardin and the MYOCARDome

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2020 · $569,541

## Abstract

Vascular smooth muscle cells (VSMCs) support nascent blood vessels during early development, but then
acquire an advanced differentiated phenotype essential for contraction and blood flow regulation. The major
effector of VSMC differentiation is the Serum Response Factor-Myocardin (SRF/MYOCD) transcriptional
switch, which binds CArG boxes found in many VSMC-restricted genes. This switch is often compromised
in disease states leading to VSMC de-differentiation. While levels of Myocardin are known to be reduced in
disease, we know virtually nothing about its regulatory control in vivo. Moreover, the downstream targets of
MYOCD (most notably, long noncoding RNAs) are not entirely known. We have generated a number of new
mouse models and enabling genomic data that allow us to rapidly define the transcriptional control of Myocd
in vivo and elucidate the function of novel SRF-dependent and SRF-independent MYOCD targets. We
propose three aims that leverage mouse models with the revolutionary CRISPR-Cas9 genome editing
system and state-of-the-art tools in genetics and genomics to test the hypothesis that SRF-dependent
and SRF-independent transcription of Myocd and the downstream MYOCARDome function to
maintain VSMC homeostasis. Aim 1 will utilize a new, biallelic-tagged Myocd mouse to interrogate
candidate enhancers and regulatory elements defined through ChIP-seq, computational prediction,
luciferase assay, or circular chromosome conformation capture (4C) assays. Two and three component
CRISPR will inform those regulatory regions of critical importance for Myocardin expression. Aim 2 will
utilize CRISPR-mediated loss-of-function mice and RNA-seq to begin deciphering the function of two novel
genes discovered in screens for MYOCD-inducibility: an SRF-dependent long noncoding RNA gene
(Mymsl) and an SRF-independent protein-coding gene (Kank1). Both genes are enriched in VSMC and
appear to function in the maintenance of normal VSMC differentiation. ChIP-seq studies will ascertain and
validate these MYOCD targets while disclosing the full MYOCARDome in VSMC using the dual epitope-
tagged mice of Aim 1. Aim 3 will further characterize the critical regulatory elements (Aim 1) and novel
MYOCD target genes (Aim 2) in models of vascular pathobiology (arterial-venous fistula and aortic
aneurysm). In addition, we will make use of new loss- and gain-of-function Myocd mice to further advance
our understanding of this critical cofactor and its downstream program in relevant models of human disease
where the VSMC differentiation program is compromised. Completion of the aims will vertically advance our
understanding of the regulatory processes undergirding Myocd expression and the function of novel
MYOCD target genes under normal and disease conditions. Such knowledge will inform the next generation
of experimental and clinical studies designed to maintain normal levels of Myocardin as a means of
thwarting the pervasive de-differentiation of VSMC observed in human dis...

## Key facts

- **NIH application ID:** 9963355
- **Project number:** 5R01HL138987-04
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Joseph M Miano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $569,541
- **Award type:** 5
- **Project period:** 2019-11-21 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963355

## Citation

> US National Institutes of Health, RePORTER application 9963355, Transcriptional Control of Myocardin and the MYOCARDome (5R01HL138987-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963355. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*