Sexual Dimorphism of the Heart: Genetics, Epigenetics, and Development

Abstract

The democratization of genomic technologies has revealed profound sex biases in expression patterns in every adult tissue, even in organs with no conspicuous differences, such as the heart. With the increasing awareness of the disparities in cardiac pathophysiology between males and females, there are exciting opportunities to explore how sex differences in the heart are established developmentally. Although sexual dimorphism is traditionally attributed to hormonal influence, expression and epigenetic sex biases observed in early cardiac development can only be accounted for by the difference in sex chromosome composition, i.e., XX in females and XY in males. In fact, genes linked to the X and Y chromosomes, many of which encode regulatory factors, are expressed in cardiac progenitor cells and at every subsequent developmental stage. The effect of the sex chromosome composition may explain why many congenital heart defects originating before gonad formation exhibit sex biases in presentation, mortality, and morbidity. Some transcriptional and epigenetic sex biases established soon after fertilization persist in cardiac lineages, suggesting that early epigenetic events are perpetuated beyond early embryogenesis. Importantly, when sex hormones begin to circulate, they encounter a cardiac genome that is already functionally distinct between the sexes. Although there is a wealth of knowledge on the effects of sex hormones on cardiac function, we propose that sex chromosome-linked genes and their downstream targets also contribute to the differences between male and female hearts. Moreover, identifying how hormones influence sex chromosome effects, whether antagonistically or synergistically, will enhance our understanding of how sex disparities are established. We also explore the possibility that sexual dimorphism of the developing heart predicts sex-specific responses to environmental signals and foreshadows sex-biased health-related outcomes after birth.

Keywords: cardiac; developmental origin of disease; embryogenesis; epigenetics; sex differences; sex-biased expression.

Figure 1

Schematic of the factors affecting sex biases in the heart across the lifespan. Sexual dimorphism exists at the molecular level from early cardiac development and across the lifespan, and is reflected in the sex biases evident in congenital heart disorders and cardiovascular health and disease. In addition to genetic, environmental and gestational factors, sex chromosome-linked genes and their interactions with hormonal effects are critical in establishing sex differences in the heart.

Figure 2

Sex biases in heart development before gonad formation. (A) Cardiac progenitors from the first and second heart fields establish the cardiac crescent during late gastrulation. Subsequent proliferation and differentiation of cells lead to the formation of a linear heart tube and cranial positioning of the atria. Remodeling then leads to chamber formation, septation, and valve development. (B) Protein-protein interaction networks were constructed from differentially expressed genes as assayed in single-cell RNA-seq experiments (84) and sex-stratified by us (83) for 8.5, 9.5, and 10.5 days post-coitum (dpc) hearts. Networks include sex-biased modules highlighted by red (female-enriched) and blue (male-enriched) nodes. Examples of sex-biased genes for 8.5, 9.5, and 10.5, respectively, include: Ctc1, Tbx2, Trim25 (female-biased); Km2a, Dusp3, Ube2c (male-biased).