# The transcriptional regulation of smooth muscle genes by PRDM6  in vascular health and diseases

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $832,899

## Abstract

Vascular smooth muscle cells (VSMCs) have a dramatic ability to alter their phenotype to adopt different roles in
diverse tissues and organs and contribute to vascular physiology, growth, remodeling, and repair. The inappropriate
SMC phenotypic modulation, however, results in a number of cardiovascular pathologies, including aortic aneurysm,
atherosclerosis, vascular malformation, systemic and pulmonary hypertension. To this date, there has been no cure
for these conditions, and surgical repair or transcatheter interventions are often associated with the recurrence of the
disease or major complications. PRDM6 is an SMC-specific epigenetic regulator that is most abundant in vascular
smooth muscle cells (VSMCs) and regulates its plasticity. Genetic variants in the PRDM6 gene have been associated
with a wide range of traits, including blood pressure regulation, reduced thoracic aortic distensibility and aortic dilation,
intracranial aneurysm, coronary artery disease, type II diabetes (T2D), BMI, and atrial flutter by genome-wide
association studies (GWAS). How PRDM6 is transcriptionally regulated and the epigenetic mechanisms by which it
regulates gene transcription are not known. Our goal is to outline the regulatory landscape of PRDM6 in the human
thoracic aorta, and identify PRDM6 enhancers that by regulating PRDM6 transcription determine the aortic diameter
by combining high throughput reporter assays with genome-wide association data. Further, we will delineate the
mechanisms of gene regulation by PRDM6 in mouse aortic SMCs (ASMCs) by genome-wide ChIPseq assays and
identify PRDM6-regulated genes in peak GWAS loci for cardiovascular diseases. Finally, we will examine the role of
Wnt signaling in aortic dilation and examine the effects of its inhibition in rescuing the trait. These findings are
expected to lead to target identification for the development of novel therapeutics for aortic aneurysms and other
diseases arising from dysregulated VSMCs, including aortic coarctations, and systemic hypertension.

## Key facts

- **NIH application ID:** 10771520
- **Project number:** 1R01HL171054-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Arya Mani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $832,899
- **Award type:** 1
- **Project period:** 2023-12-11 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10771520

## Citation

> US National Institutes of Health, RePORTER application 10771520, The transcriptional regulation of smooth muscle genes by PRDM6  in vascular health and diseases (1R01HL171054-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10771520. Licensed CC0.

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