Human-gained heart enhancers are associated with species-specific cardiac attributes

Heart development is controlled by a relatively conserved network of transcriptional and chromatin regulators; how the human heart has evolved species-specific features to maintain adequate cardiac output and function remains to be defined. In this study, we performed a comparative epigenomic analysis of mouse and human cardiomyocytes at the earliest stages of cardiogenesis and identified enhancers and promoters that are specifically active in human cardiogenesis. These cis-regulatory elements (CREs) are associated with genes involved in heart development and function and are enriched in genetic variants associated with human cardiac phenotypic and disease traits, particularly those differing between humans and mice. Human-gained CREs are also gained within genomic loci of known transcriptional regulators, potentially expanding their role in human heart development. In particular, we found that a human-gained enhancer in the locus of the early developmental regulator ZIC3 regulates ZIC3 induction at the mesoderm stage as well as cardiomyocyte differentiation. Overall, our results illuminate how human-specific CREs can contribute to human-specific cardiac attributes and can expand the role of conserved transcriptional regulators in human cardiac development. Destici, Zhu, et al. identify human-specific cis-regulatory elements (CREs) through a comparative epigenomic analysis of human and mouse cardiomyocytes at early stage of development and show that these CREs could contribute to species-specific cardiac features. Human-specific enhancers were particularly enriched in SNPs associated with human-specific traits (such as increased heart resting rate, atrial fibrillation and QRS duration), and the acquisition of human-specific enhancers could expand the functionality of the conserved transcriptional regulator ZIC3 by modifying its spatio-temporal expression.