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

哺乳动物早期发育中雄性和雌性差异的遗传蓝图

• 批准号: 1933738
• 负责人: Nora Engel
• 金额: $ 108万
• 依托单位: Temple University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1933738&HistoricalAwards=false
• 关键词: Genetic; Blueprint; Differences; Between; Males

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.

虽然雄性和雌性哺乳动物的生殖器官不同，但心脏和肺等其他器官似乎是相同的。然而，当观察在任何器官的男性和女性细胞中表达的基因时，就会有实质性的差异。其中一些是因为雌性细胞有两条X染色体，而雄性细胞有一条X染色体和一条Y染色体。此外，性腺产生的荷尔蒙可以影响基因的表达。这些分子差异是如何建立的，以及它们是如何影响功能的，目前尚不清楚。这个项目的目的是通过研究胚胎发育的连续阶段的基因表达和表观遗传学特征，来研究从受精后不久开始到整个胚胎发育过程中雄性和雌性小鼠之间的分子差异。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如何塑造男性和女性的基因和荷尔蒙差异。该项目包括外展和教育项目，以提高研究生和本科生对男性和女性生理差异的认识。该项目还将为本科生提供实践研究经验的培训机会。此外，它还将有助于创建一种资源，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较低的背景，特别是在STEM学科。受精后不久，X和Y染色体编程常染色体基因表达和表观基因组图谱，建立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，也不清楚男性和女性的偏见是如何在不同的发育阶段和不同的谱系中演变的。该项目的目标是通过整合体外和体内的实验和系统水平分析来填补这一知识空白。它检验了这样一种假设，即编码在X和Y染色体上的调节因子决定了常染色体基因的差异表达和表观遗传学特征。荷尔蒙抵消了这些差异中的一些，但另一些仍然存在，甚至在成年生物体中也会影响细胞表型。这一假说将通过：1)确定早期胚胎发育中差异表达的调控因子的转录和表观遗传效应；以及2)确定性腺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。由于在早期发育阶段建立的表观遗传标记可能是潜在的，并与后期的基因表达相关，因此这项研究也将成为理解胚胎发生过程中的事件如何影响出生后及以后的二型性的范例。此外，这些研究将为转录和表观遗传因子剂量对转录的影响的机制研究奠定基础。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

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

• DOI: 10.3389/fcvm.2021.668252
• 发表时间: 2021
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Deegan DF;Nigam P;Engel N
• 通讯作者: Engel N