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Single-nucleus epigenomic atlas provides roadmap for understanding heart disease

Many cardiovascular disease (CVD) risk variants lie in noncoding sequences, yet little is known about how such variants participate in the development of CVD. A major reason for this is the lack of single cell-resolved generegulatory maps of the heart. Recognizing this knowledge gap, Dr. Neil Chi, Professor of Medicine and Director of the UCSD Cardiovascular Genetics Clinic and Cardiac Tissue Harvest and Biorepository Core, the Center and the lab of the Center’s Director Dr. Bing Ren partnered to generate the first, single cell-resolved epigenomic atlas of the human heart. But first, they had to figure out how to optimize the Center’s single-cell technologies to address the unique challenges posed by human heart tissue.

SINGLE-NUCLEUS EPIGENOMIC ATLAS PROVIDES ROADMAP FOR UNDERSTANDING HEART DISEASE

“Intact cardiomyocytes cannot be isolated from frozen heart tissue,” said Sebastian Preissl, Associate Director for Single Cell Genomics at the Center, adding that the cells are also too large for existing single-cell droplet partitioning systems. As a workaround, Preissl resorted to isolating individual nuclei instead. But the challenges didn’t end there: “Nobody had done single-nucleus ATAC-seq on human heart samples,” Preissl recounted. “So we had to figure out how to prepare nuclei from frozen tissue in a way compatible with our assay.” Preissl and James Hocker, a graduate student of Bing Ren’s lab, leveraged the Center’s expertise to quickly optimize the single-nucleus ATAC-seq assay for frozen human heart tissue.

The end result — a comprehensive, single-nucleus atlas of cis-regulatory elements of the human heart — was recently published in Science Advances. Chi reflected on the impact of the new dataset: “We can now use these maps to start addressing a key issue of human genetics: to finally understand the impact of variants that we’ve known about for quite some time.”

Moving forward, Chi and Preissl said they’d like to start utilizing newer multi-omics technologies, and profile diseased human heart tissue to delve deeper into the gene-regulatory networks that underlie CVD. Multi-omics technologies provide joint profiling of transcriptional and epigenomic information in the same individual cell. These new tools are poised to provide even deeper insight into gene regulatory programs than is possible with individual single-cell assays.

Chi’s ongoing collaboration with the Center aims to clarify a number of outstanding questions. How do gene regulatory networks in human heart cell types change in disease? Which risk variants are pathogenic? Can new biomarkers be identified? What about therapeutic targets? “The technologies being developed by the Center are allowing us to begin answering these questions,” said Chi.