Potential genetic regulators of the heartbeat identified
Researchers in the US have mapped gene control elements in specialised cardiac cells responsible for co-ordinating heartbeats.
The findings of the genome exploration study by researchers at UT Southwestern Medical Center, published in The Journal of Clinical Investigation, provide insight into how heartbeats are regulated and could impact diagnosis and risk prediction for a variety of common arrhythmias.
“Our study provides the first road map for all the gene-control elements in the specialised population of cardiomyocytes responsible for cardiac rhythm,” said corresponding author Nikhil Munshi, M.D., Ph.D., Associate Professor of Internal Medicine, Molecular Biology, in the Eugene McDermott Center for Human Growth and Development (pictured), and Assistant Director of the Division of Cardiology’s Physician Scientist Training Program.
“Among other things, we showed that this information enables us to better understand how certain non-coding, genomic variants in the human population influence a given individual’s unique heart properties.”
The cardiac conduction system, which comprises about 1 per cent to 5 per cent of the heart cell population, coordinates a series of electrical impulses to ensure efficient heartbeat and blood circulation.
Failure of this system to work properly can result in arrhythmias such as atrial fibrillation, sinus bradycardia, atrioventricular block, and ventricular tachycardia.
Despite this vital function, little is known about the genetics and molecular makeup of this small group of heart cells.
Dr Munshi and his team of UT Southwestern researchers sought to determine the control components of the cardiac conduction system.
Using a technique previously developed by the Munshi lab (PAN-INTACT) and published in PLoS One, the team isolated nuclei – which contain the cells’ genetic material – from mouse cardiac conduction system cells.
Using a second method called ATAC-Seq, they identified parts of the genome that control gene expression, known as cis-regulatory elements (CREs).
The researchers gathered their results to establish a CRE database that can be used to better understand the functions of these cells and how they’re regulated and help to interpret human variants associated with arrhythmias.
The study has two immediate clinical implications, Dr Munshi said: It will facilitate easier interpretation of clinical whole genome sequencing results in patients with familial arrhythmias, and it will enable future risk evaluation for common arrhythmias.
Moreover, these results will help formulate hypotheses about how certain arrhythmias arise and potentially how they can be treated in the future.
Other UT Southwestern researchers who contributed to this work include Samadrita Bhattacharyya, Rahul K. Kollipara, Ralf Kittler, Gabriela Orquera-Tornakian, Sean Goetsch, Minzhe Zhang, Cameron Perry, Boxun Li, John M. Shelton, Minoti Bhakta, Jialei Duan, Yang Xie, Guanghua Xiao, Bret M. Evers, and Gary C. Hon.
This work was supported by a Burroughs Wellcome Fund Career Award for Medical Scientists (1009838). Additional funding was provided by the American Heart Association (17PCRE33670730), the National Institutes of Health (HL136604, HL133642, HL135217, and CA200787), the March of Dimes Foundation (5-FY13-203), the Department of Defense (PR172060), the Cancer Prevention and Research Institute of Texas (R1002), and the John L. Roach Endowment in Biomedical Research.
Dr. Kittler is the John L. Roach Scholar in Biomedical Research. Dr. Xiao holds the Mary Dees McDermott Hicks Chair in Medical Science. Dr. Xie holds the Raymond D. and Patsy R. Nasher Distinguished Chair in Cancer Research, in honor of Eugene P. Frenkel, M.D.