The developmental origins of sex-biased expression in cardiac development

Abstract

Background Expression patterns between males and females vary in every adult tissue, even in organs with no conspicuous dimorphisms such as the heart. While studies of male and female differences have traditionally focused on the influence of sex hormones, these do not account for all the differences at the molecular and epigenetic levels. We previously reported that a substantial number of genes were differentially expressed in male and female mouse embryonic stem (ES) cells and revealed dose-dependent enhancer activity in response to Prdm14 , a key pluripotency factor expressed more highly in female ES cells. In this work, we investigated the role of Prdm14 in establishing sex-specific gene expression networks. We surveyed the sex-specific landscape in early embryogenesis with special reference to cardiac development. We generated sex-specific co-expression networks from mouse ES cells, examined the presence of sex-specific chromatin domains, and analyzed previously published datasets from different developmental time points to characterize how sex-biased gene expression waxes and wanes to evaluate whether sex-biased networks are detectable throughout heart development. Results We performed ChIP-seq on male and female mouse ES cells to determine differences in chromatin status. Our study reveals sex-biased histone modifications, underscoring the potential for the sex chromosome complement to prime the genome differently in early development with consequences for later expression biases. Upon differentiation of ES cells to cardiac precursors, we found sex-biased expression of key transcription and epigenetic factors, some of which persisted from the undifferentiated state. Using network analyses, we also found that Prdm14 plays a prominent role in regulating a subset of dimorphic expression patterns. To determine whether sex-biased expression is present throughout cardiogenesis, we re-analyzed data from two published studies that sampled the transcriptomes of mouse hearts from 8.5 days post-coitum embryos to neonates and adults. We found sex-biased expression at every stage in heart development, and interestingly, identified a subset of genes that exhibit the same bias across multiple cardiogenic stages. Conclusions Overall, our results support the existence of sexually dimorphic gene expression profiles and regulatory networks at every stage of cardiac development, some of which may be established in early embryogenesis and epigenetically perpetuated. Electronic supplementary material The online version of this article (10.1186/s13293-019-0259-1) contains supplementary material, which is available to authorized users.

Dysregulation of microRNA Modulatory Network in Abdominal Aortic Aneurysm

“…Some of proposed miRNA biomarkers of AAA have already been connected to sex differences in humans ( Table A2 in Appendix D ), suggesting that deregulation of these miRNAs may reflect gender differences occurring between AAA and control group. In the case of gene expression, comparison of Deegan et al paper [ 61 ] draw only five overlapping genes, suggesting minor gender bias, while from [ 62 ] there were no such ones ( Table A3 in Appendix E ). Interestingly, Cui et al discovered that blood is poor material for distinguishing sex associated transcriptome patterns due to relative invariability between genders [ 63 ].…”

“… No. Gene Symbol Association with Gender Association with Smoking [ 61 ] 1 [ 62 ] [ 113 ] 2 [ 114 ] 3 [ 115 ] 4 [ 116 ] 5 [ 117 ] 5 [ 118 ] 5 [ 119 ] [ 120 ] Upregulated genes 1 CPT1A no no no no no no no no no no 2 GGT1 no no no no no no no no no no 3 …”

Sex Chromosomes and Sex Phenotype Contribute to Biased DNA Methylation in Mouse Liver

“…However, comparisons of females with different genetic sex (XX.F vs. XY.F) yield very few DEGs ( Figure 5 a). This rather limited the influence of the sex-chromosome complement on the liver transcriptome is in striking contrast to its prominent effects on intestinal lipid metabolism [ 75 ], the transcriptomes of the mouse thymus [ 2 ] and heart [ 7 ], or the methylation and expression patterns in human blood cells [ 4 , 15 ]. There is also a remarkable difference between autosomal and X-linked sDMR with respect to their relationship with DEGs.…”

“…In general, more DEGs were detected in comparisons between groups with different phenotypic sex (XX.F vs. XY.M and XY.F vs. XY.M) than between groups with the same phenotypic sex, but different sex-chromosome complements (XX Paf .F vs. XO.F and XX.F vs. XY.F), which is consistent with the relative numbers of sDMR detected. Larger portions of DEGs showed lower expression levels on chromosome 5,7,10,12,15,19, and X in males in the XX.F versus XY.M and XY.F versus XY.M comparisons, while DEGs on Y chromosomes all were detected only in Y chromosome carriers in both XX.F versus XY.M and XX.F versus XY.F comparisons (Figure 5a). Out of the 290 DEGs in the XX.F versus XY.M comparison, 172 overlapped with DEGs in the XY.F versus XY.M, 14 with the XX.F versus XY.F, and 2 with the XX Paf .F versus XO.F (Figure 5b).…”

“…The gonadal sex of the mouse has a major effect on gene expression levels in mouse liver [1,6]. In contrast, the sex-chromosome complement drives sex-biased gene expression in mouse embryonic stem cells, adult mouse thymus or heart, as well as human peripheral blood cells [2][3][4]7]. Thus, data from both mouse and human studies suggest a complex regulation of sexually dimorphic gene expression where the roles of gonadal sex hormones and sex chromosomes vary between different tissues and developmental stages.…”