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.

中文翻译：

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心脏发育中性别偏向表达的发育起源。

背景技术在每个成体组织中，雄性和雌性之间的表达模式各不相同，甚至在没有明显二态性的器官（例如心脏）中也是如此。虽然对男性和女性差异的研究传统上集中在性激素的影响上，但这些并不能解释分子和表观遗传水平上的所有差异。我们之前报道过，大量基因在雄性和雌性小鼠胚胎干 (ES) 细胞中存在差异表达，并揭示了对 Prdm14 的剂量依赖性增强子活性，Prdm14 是一种关键的多能性因子，在雌性 ES 细胞中表达更高。在这项工作中，我们研究了 Prdm14 在建立性别特异性基因表达网络中的作用。我们调查了早期胚胎发生中的性别特异性景观，特别是心脏发育。我们从小鼠 ES 细胞中生成了性别特异性共表达网络，检查了性别特异性染色质域的存在，并分析了之前发布的不同发育时间点的数据集，以表征性别偏向基因表达的盛衰情况，以评估性别是否与性别相关。在心脏发育过程中可以检测到有偏见的网络。结果我们对雄性和雌性小鼠 ES 细胞进行 ChIP-seq 以确定染色质状态的差异。我们的研究揭示了性别偏向的组蛋白修饰，强调了性染色体补体在早期发育中以不同方式启动基因组的潜力，并对以后的表达偏向产生影响。在 ES 细胞分化为心脏前体细胞时，我们发现关键转录和表观遗传因子的性别偏向表达，其中一些在未分化状态下持续存在。通过网络分析，我们还发现 Prdm14 在调节二态性表达模式的子集方面发挥着重要作用。为了确定整个心脏发生过程中是否存在性别偏向表达，我们重新分析了两项已发表研究的数据，这两项研究对小鼠心脏的转录组进行了采样，从性交后 8.5 天的胚胎到新生儿和成人。我们发现心脏发育的每个阶段都存在性别偏向性表达，有趣的是，我们还发现了在多个心源性阶段表现出相同偏向性的基因子集。结论 总的来说，我们的结果支持心脏发育的每个阶段都存在性二态性基因表达谱和调控网络，其中一些可能在早期胚胎发生中建立并在表观遗传上永久存在。