The Human Genome Project marked a major milestone in the scientific community as it unravelled the ~3 billion bases that are central to crucial aspects of human life. Despite this achievement, it only scratched the surface of understanding how each nucleotide matters, both individually and as part of a larger unit. Beyond the coding genome, which comprises only ~2% of the whole genome, scientists have realized that large portions of the genome, not known to code for any protein, were crucial for regulating the coding genes. These large portions of the genome comprise the ‘non-coding genome’. The history of gene regulation mediated by proteins that bind to the regulatory non-coding genome dates back many decades to the 1960s. However, the original definition of ‘enhancers’ was first used in the early 1980s. In this Review, we summarize benchmark studies that have mapped the role of cardiac enhancers in disease and development. We highlight instances in which enhancer-localized genetic variants explain the missing link to cardiac pathogenesis. Finally, we inspire readers to consider the next phase of exploring enhancer-based gene therapy for cardiovascular disease.

人类基因组计划标志着科学界的一个重要里程碑，因为它揭示了对人类生命的关键方面至关重要的约 30 亿个碱基。尽管取得了这一成就，但它只是触及了对每个核苷酸如何重要的理解的表面，无论是单独的还是作为一个更大单元的一部分。除了仅占整个基因组约 2% 的编码基因组之外，科学家们已经意识到基因组的大部分（未知编码任何蛋白质）对于调节编码基因至关重要。基因组的这些大部分组成了“非编码基因组”。由与调节性非编码基因组结合的蛋白质介导的基因调节的历史可以追溯到几十年前的 1960 年代。然而，“增强剂”的最初定义是在 80 年代初期首次使用的。在这篇评论中，我们总结了标杆研究，这些研究描绘了强心剂在疾病和发育中的作用。我们强调增强子定位的遗传变异解释与心脏病发病机制的缺失联系的实例。最后，我们鼓励读者考虑探索基于增强子的心血管疾病基因治疗的下一阶段。