Experts develop new single-cell “chromatin atlas” of the human genome

Researchers from the University of Virginia School of Medicine have developed a crucial new tool that provides a better understanding of how genes in particular cells affect the risk of developing heart disease, the world’s leading cause of death. The new single-cell “chromatin atlas” of the human genome will help researchers better understand how genes are activated or inactivated in various situations.

More than 200 distinct genetic markers linked to the risk of coronary artery disease have already been discovered by scientists. However, because they are located in regions of the genome that contain a type of DNA that is poorly understood and was once thought to be “junk,” it is challenging to interpret the impact that these variants have on disease risk.

Although making proteins has traditionally been thought to be the primary function of DNA, this type of DNA also plays a significant role in controlling the activity of other genes.

The newly developed chromatin atlas, created in the laboratory of Clint L. Miller, PhD, and associates at UVA, opens a perspective into these so-called “non-coding” variants and may aid in the comprehension of the intricate effects they have on the regulation of genes linked to coronary artery disease.

This new atlas will help us narrow down the cell types responsible for gene regulation in the heart vasculature. It will also provide a roadmap for interpreting non-coding disease variants in the most relevant tissue. Knowing how these variants operate via cell type-specific regulatory elements should help facilitate both mechanistic and translational studies across the coronary artery disease spectrum.”

Clint L. Miller, Center for Public Health Genomics, University of Virginia

Miller is also associated with UVA’s Departments of Biochemistry and Molecular Genetics and Public Health Sciences.

Targeting coronary artery disease

Heart disease includes conditions like coronary artery disease. It happens when there is a buildup of plaque inside the lining of the heart’s arteries, which is frequently brought on by cholesterol. The arteries become more narrow as the plaque accumulates. This reduces the amount of oxygen-rich blood reaching the body’s major organs, which may cause a heart attack or even death.

The risk of developing coronary artery disease over the course of a person’s lifetime is influenced by both genetics and environmental factors. Researchers may be able to create more specialized or preventative treatments if they have a better understanding of the genes that contribute to driving disease risk in its early stages.

Using the state-of-the-art single-cell sequencing technology, we have increased the resolution of this atlas to an unprecedented level. For the first time, we are able to directly study chromatin factors that potentially control coronary artery disease genes in thousands of individual cell nuclei.”

Chongzhi Zang PhD, Study Co-Author and Member, Center for Public Health Genomics, University of Virginia

Chongzhi Zang is also associated with UVA’s Departments of Biochemistry and Molecular Genetics and Public Health Sciences.

The chromosomes’ chromatin, which is made up of DNA and proteins, is essential for controlling the activity of genes. In this instance, the new chromatin atlas will help scientists comprehend how chromatin regulates the genes that cause coronary artery disease.

By pinpointing the genes that can cause disease, we may ultimately be able to develop more effective interventions tailored to an individual’s risk profile. Our work aims to advance our ability to target genes in specific cells or cell types.”

Clint L. Miller, Center for Public Health Genomics, University of Virginia

Miller and colleagues profiled more than 28,000 nuclei using coronary artery segments from 41 patients with various stages of coronary artery disease. They found 14 distinct clusters that represented various cell types, including smooth muscle cells, endothelial cells, and immune cells.

Additional investigations revealed over 320,000 regulatory elements and transcription factors that control how RNA molecules turn on or off to make proteins or perform other tasks at the cellular level.

Miller and associates used this technique to record the regulatory profiles of several significant genes, including PRDM16 and TBX2. These genes, transcriptional regulators that have been linked to cardiovascular processes, may contribute to the onset of coronary artery disease in a person.

Miller concludes, “We hope this resource will enable others to investigate the complex mechanisms of coronary artery disease in different cell types and model systems. This work would not have been possible without interdisciplinary collaborations and study participants, and we look forward to extending similar resources to the cardiovascular community.”