A Genetic Blueprint for Differences Between Males and Females in Early Mammalian Development

虽然雄性和雌性哺乳动物有不同的生殖器官，但其他器官，如心脏和肺，似乎是相同的。然而，当观察任何器官中男性和女性细胞中表达的基因时，就会发现存在实质性的差异。其中一些是由于女性细胞有两条X染色体，而男性细胞有一条X染色体和一条Y染色体。此外，性腺产生的激素可以影响基因的表达。这些分子差异是如何形成的以及它们如何影响功能尚不清楚。本项目的目的是通过表征胚胎发生连续阶段的基因表达和表观遗传特征，研究雄性和雌性小鼠在受精后不久和整个胚胎发育过程中的分子差异。所产生的数据将允许与其他模式生物进行比较研究，并有助于深入了解进化是如何形成男性和女性基因和激素差异的。该项目包括推广和教育项目，以提高对研究生和本科生男女生理差异的认识。该项目还将为本科生提供实践研究经验的培训机会。此外，它将有助于创建一个资源，培训学生向该地区的高中生教授基因组和生物信息学概念。这些学生通常来自代表性不足的背景，尤其是在STEM学科。受精后不久，X和Y染色体就开始控制常染色体基因表达和表观基因组景观，建立了男性和女性特有的基因网络。这些影响背后的机制尚不清楚，以及男性和女性偏见是如何在发展过程中和不同谱系中进化的。该项目的目标是通过在体外和体内整合实验和系统级分析来填补这一知识空白。它检验了在X和Y染色体上编码的调节因子决定常染色体基因的差异表达和表观遗传谱的假设。激素平衡了其中的一些差异，但其他差异仍然存在，甚至在成年生物体中也会影响细胞表型。这一假设将通过以下方法得到验证：1)确定早期胚胎发生中差异表达调控因子的转录和表观遗传效应；2)确定性激素出现前后依赖于X和Y染色体的基因表达和表观遗传模式的偏差。这些实验将利用一种小鼠模型，该模型允许分离雄性和雌性表型的遗传和激素成分。由于在早期发育中建立的表观遗传标记可能是潜在的，并且与后期的基因表达相关，因此本研究也将作为理解胚胎发生事件如何影响出生后及以后的二态性的范例。此外，这些研究将为进一步研究转录和表观遗传因子剂量对转录组的影响机制奠定基础。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Although male and female mammals have different reproductive organs, other organs, such as the heart and lungs, seem to be identical. However, when looking at the genes being expressed in male and female cells in any organ, there are substantial differences. Some of these are due to the fact that female cells have two X chromosomes and males have one X and one Y chromosome. In addition, the hormones produced by the gonads can influence the genes expressed. How these molecular differences are established and how they affect functionality is not known. The objective of this project is to investigate the molecular differences between male and female mice, starting soon after fertilization and throughout embryonic development by characterizing gene expression and epigenetic features at successive stages of embryogenesis. The data generated will allow comparative studies with other model organisms and lend insight into how evolution has shaped male and female genetic and hormonal differences. The project includes outreach and educational programs to increase awareness of how male and female physiologies differ among students, both at the graduate and undergraduate level. This project will also provide training opportunities for undergraduate hands-on research experiences. In addition, it will contribute towards creating a resource to train students to teach genomic and bioinformatic concepts to high school students in the area. These students are generally from underrepresented backgrounds, especially in the STEM disciplines.Beginning soon after fertilization, the X and Y chromosomes program autosomal gene expression and the epigenomic landscape, establishing male- and female-specific gene networks. The mechanisms underlying these effects are unknown, as well as how male and female biases evolve across development and in different lineages. The objective of this project is to fill this knowledge gap by integrating experimental and systems level analyses in vitro and in vivo. It examines the hypothesis that regulatory factors encoded on the X and Y chromosomes dictate differential expression and epigenetic profiles of autosomal genes. Hormones equalize some of these differences, but others persist, affecting cellular phenotypes even in the adult organism. This hypothesis will be tested by: 1) determining the transcriptional and epigenetic effects of differentially expressed regulatory factors in early embryogenesis; and 2) identifing the biases in gene expression and epigenetic patterns dependent on the X and Y chromosomes before and after the appearance of gonadal hormones. These experiments will exploit a mouse model that allows segregation of the genetic and hormonal components of the male and female phenotypes. Since epigenetic marks established in early development can be latent and relevant to gene expression at later stages, this research will also serve as a paradigm for understanding how events in embryogenesis influence dimorphisms after birth and beyond. Moreover, these studies will lay the groundwork for mechanistic studies on the effects of transcription and epigenetic factor dosage on the transcriptome.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.