Related Experiment Video
Updated: Feb 7, 2026
08:24
Isolation of Murine Coronary Vascular Smooth Muscle Cells
Published on: May 30, 2016
14.8K
Allelic Variation at 9p21.3 Orchestrates Widespread RNA Splicing Shifts Governing Vascular Smooth Muscle Cell
S Suryavanshi1, H Yang1, E Salido1
1Department of Cell and Regenerative Biology; University of Wisconsin-Madison; Madison, WI 53705, USA.
Biorxiv : the Preprint Server for Biology
|February 6, 2026
Summary
The 9p21.3 genetic locus strongly influences coronary artery disease (CAD) risk by altering vascular smooth muscle cell (VSMC) splicing and phenotype. Targeting the DDX5 gene can mitigate this risk, offering new therapeutic avenues for cardiovascular disease.
Area of Science:
- Genetics
- Cardiovascular Biology
- Molecular Biology
Background:
- The 9p21.3 genomic locus is the most significant genetic risk factor for coronary artery disease (CAD), yet its cellular mechanisms remain elusive.
- Understanding how this locus affects vascular cells is crucial for developing targeted CAD therapies.
Purpose of the Study:
- To investigate the functional impact of the 9p21.3 locus on vascular smooth muscle cells (VSMCs).
- To compare the transcriptomic and splicing differences between CAD risk and non-risk haplotypes at 9p21.3.
- To identify molecular targets for mitigating CAD risk associated with the 9p21.3 locus.
Main Methods:
- Haplotype-biased genome editing in induced pluripotent stem cells (iPSCs) followed by differentiation into VSMCs.
- Long-read RNA sequencing to analyze allele-specific transcriptional programs and splicing.
- Functional validation of candidate genes, including DDX5, in VSMCs.
Main Results:
- Distinct allele-specific transcriptional programs and extensive mRNA splicing reprogramming were identified between risk and non-risk 9p21.3 haplotypes.
- The risk haplotype induces aberrant VSMC phenotypic modulation, promoting a pro-calcification and osteochondrogenic state.
- Disruption of transcript isoform expression in CAD-related genes, including DDX5, was observed.
- Modulating DDX5 expression in VSMCs ameliorated the risk-associated cellular phenotype.
Conclusions:
- The 9p21.3 locus significantly impacts VSMC phenotype through allele-specific regulation of transcription and alternative splicing.
- A 9p21.3-DDX5 axis is proposed as a key regulator of VSMC phenotypic plasticity and CAD risk.
- This study provides novel insights into CAD pathogenesis and identifies targetable transcripts for cardiovascular risk reduction.
Related Concept Videos
02:18Alternative RNA Splicing
25.2K
Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
25.2K
02:18Alternative RNA Splicing
5.2K
5.2K
01:32RNA Splicing
60.7K
Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
60.7K
01:23Functions of Smooth Muscles
3.4K
Smooth muscles are an important type of muscle tissue that plays a vital role in the involuntary movements of internal organs. For example, they help regulate the movement of food through the gut and the flow of blood through the circulatory system.
Function of visceral smooth muscles
Visceral smooth muscle is found in the walls of all hollow organs, except the heart, and is a key player in the involuntary movements that drive the functioning of these internal organs. This tissue is arranged in...
Function of visceral smooth muscles
Visceral smooth muscle is found in the walls of all hollow organs, except the heart, and is a key player in the involuntary movements that drive the functioning of these internal organs. This tissue is arranged in...
3.4K
01:25Smooth Muscle Contraction
7.8K
Smooth muscle contraction is a complex process vital for various bodily functions, from maintaining blood vessel tension to facilitating the movement of food through the digestive tract. Unlike striated muscles, smooth muscle contraction begins more slowly and lasts longer.
The onset of contraction is triggered by an increase in calcium ions within the sarcoplasm, similar to the process in striated muscle. However, smooth muscles have a relatively smaller reservoir of the sarcoplasmic...
The onset of contraction is triggered by an increase in calcium ions within the sarcoplasm, similar to the process in striated muscle. However, smooth muscles have a relatively smaller reservoir of the sarcoplasmic...
7.8K
02:41Chromatin Structure and RNA Splicing
3.5K
3.5K