Heart Function Suffers When Enhancer DNA Is Disabled

    Heart disease isn’t just about genes. It’s about gene expression, too, as scientists based at Lawrence Berkeley National Laboratory have demonstrated. These scientists examined the how noncoding DNA elements called enhancers can impact heart function. They identified two enhancers that appear to be relevant to human heart development and function, and then they disabled either one of these enhancers (or rather their equivalents) in mice. The result? Experimental animals with flagging hearts.

    Details of the work appeared October 5 in the journal Nature Communications, in an article entitled, “Genome-Wide Compendium and Functional Assessment of In VivoHeart Enhancers.” The article describes how the Berkeley Lab scientists surveyed the genome-wide landscape of distant-acting enhancers active in the developing and adult human heart. Using integrative analysis of >35 epigenomic datasets from mouse and human pre- and postnatal hearts, the scientists created a comprehensive reference of >80,000 putative human heart enhancers.

    “To illustrate the importance of enhancers in the regulation of genes involved in heart disease, we deleted the mouse orthologs of two human enhancers near cardiac myosin genes,” the authors indicated. “In both cases, we observe in vivo expression changes and cardiac phenotypes consistent with human heart disease.”

    Specifically, the scientists observed symptoms resembling human cardiomyopathy, a disease in which the heart muscle often becomes enlarged or rigid. The scientists used echocardiograms to image the hearts from control and experimental mice to confirm that the heart tissue of mice with a disabled enhancer was pumping with less power than normal.

    “The cardiac changes that we observed in knockout mice lacking these enhancers highlight the role of noncoding sequences in processes that are important in human disease,” said the study’s co-senior author Axel Visel, Ph.D., a senior staff scientist at Berkeley Lab’s Environmental Genomics and Systems Biology Division. “Identifying and interpreting sequence changes affecting noncoding sequences is increasingly a challenge in human genetics. The genome-wide catalog of heart enhancers provided through this study will facilitate the interpretation of human genetic datasets.”

    To assess the function of heart enhancers, the researchers first compiled a single road map to guide them. They used results from a technology called ChIP-seq (chromatin immunoprecipitation sequencing) to identify the likely heart enhancers in the human genome.

    The researchers asserted that this map will become an important tool as advances in genomics usher in a new era of personalized medicine. “This compendium of human heart enhancers,” explained Diane Dickel, Ph.D., the study’s lead author and a project scientist at Berkeley Lab, “will be a valuable resource for many disease researchers who have begun adopting whole-genome sequencing of patients to look for disease-causing mutations in both the coding and noncoding portion of the genome.”

    “Prior to this work, no study had looked at what happens to heart function as a result of knocking out the heart enhancers in the genome,” Dr. Dickel continued. “What was surprising to me was that outwardly, the knockout mice seemed fine. If you just looked at them, you wouldn’t necessarily see anything wrong.”

    With so many enhancers to test, the map could help scientists prioritize which ones to assess in animal studies and in disease research, the researchers concluded.