Spermatogenic gene regulation and infertility

康奈尔生殖基因组学中心（CRG）成立于2007年，其目标是利用国家的 了解哺乳动物生殖细胞生物学的最先进的基因组学技术。更具体地说，我们的 目标是了解产生可行的基因，表观遗传和表观转录组学基础。 健康的配子，并探讨如何改变这些事件可能有助于人类不育。公 已知调控基因表达所有方面（包括染色质）所需基因的破坏 修饰物、转录机制和转录后调节途径的组分，导致 在小鼠中形成具有异常头部形态的精子，而来自男性的精子增加 精子形态异常者染色体非整倍体率明显增高，染色质致密化 缺陷和改变的转录组谱相比，精子从生育男性。因此，在本申请中，我们 试图了解如何转录，转录后，和epitranscriptomic调控基因表达 染色质状态有助于单倍体生殖细胞分化为成熟精子。三 提出了三个项目，并提出了三个核心。项目I（Danko和Cohen）将侧重于 在减数分裂退出和进入减数分裂时基因表达转录调控的重要性 精子发生，重点是布罗莫结构域蛋白，BRDT在促进转录 关闭，从而允许适当的组蛋白-鱼精蛋白替代和核致密化。 项目II（Grimson，Schimenti，Hwang）将侧重于转录后的机制和功能， 精子发生过程中mRNA的加工和调节，以及这些过程中的缺陷是否可以 寻求辅助生殖技术的患者精子形态缺陷的基础。项目三 （Jaffrey）将探索N6-甲基腺苷（M6 A）和N6，2 '-O-二甲基腺苷（m6 Am）的动力学 通过小鼠和男性精子发生对RNA的修饰，以及这些修饰的重要性。 在小鼠和男性中产生健康精子的表观变化。这些研究将得到支持 由一个完善的行政核心（科恩），将促进密切的互动，通过定期 会议、实习生活动、试点和种子赠款，以及我们广受欢迎的“三重”年度研讨会。我们的国家- 最先进的基因组创新核心（Grenier）将作为一个创新中心，探索 生殖基因调控，专门从事一系列下一代测序技术，以支持 项目。最后，我们的外展核心（林）将提供实验室的机会，附近，传统上， 服务不足，整个纽约北部的学区，同时派遣我们的学员和教师 作为年轻科学家的榜样。我们的中心将受益于强者 我们在过去13年中建立的研究和临床整合， 机构的支持，并由康奈尔大学提供的优秀的科学环境。

The Cornell Center for Reproductive Genomics (CRG) was founded in 2007 with the goal of leveraging state-of- the-art genomics technologies for understanding the biology of the mammalian germ cell. More specifically, our goal has been to understand the genetic, epigenetic, and epitranscriptomic basis for the generation of viable healthy gametes and to explore how alterations in these events could contribute to human infertility. It is well known that disruption of genes required for regulating all aspects of gene expression, including chromatin modifiers, the transcription machinery, and components of post-transcriptional regulatory pathways, leads to the formation of spermatozoa with abnormal head morphology in the mouse, while sperm from men with increased abnormal sperm morphology significantly higher rates of chromosomal aneuploidy, chromatin compaction defects, and altered transcriptome profiles compared to sperm from fertile men. Thus, in this application, we seek to understand how transcriptional, post-transcriptional, and epitranscriptomic regulation of gene expression and chromatin state contributes to the differentiation of haploid germ cells into mature spermatozoa. Three projects are proposed and three cores are proposed. PROJECT I (Danko and Cohen) will focus on the importance of transcriptional regulation of gene expression at the exit from meiosis and entry into spermiogenesis, with a focus on the role of the bromodomain protein, BRDT in facilitating transcriptional shutdown and thus permitting appropriate histone-to-protamine replacement and nuclear compaction. PROJECT II (Grimson, Schimenti, Hwang) will focus on mechanisms and functions of post-transcriptional processing and regulation of mRNAs during spermiogenesis and whether defects in these processes can underlie defects in sperm morphology in patients seeking assisted reproductive technologies. PROJECT III (Jaffrey) will explore the dynamics of N6-methyladenosine (M6A) and N6, 2’-O-dimethyladenosine (m6Am) modifications on RNA through spermatogenesis in mice and in men, and the importance of these epitranscriptomic changes for the production of healthy sperm in mice and men. These studies will be supported by a well-established ADMINISTRATIVE CORE (Cohen) that will facilitate close interactions through regular meetings, trainee events, pilot and seed grants, and our popular “Tri-Repro” Annual Symposium. Our state-of- the-art GENOME INNOVATION CORE (Grenier) will serve as an Innovation Hub for exploring all aspects of gene regulation in reproduction, specializing in a range of next generation sequencing technologies to support the projects. Finally, our OUTREACH CORE (Lin) will provide lab opportunities for nearby, and traditionally underserved, school districts throughout upstate New York, at the same time sending our trainees and faculty out to these communities as role models for young budding scientists. Our center will benefit from the strong research and clinical integration we have established over the past 13 years, by robust and unequivocal institutional support, and by the outstanding scientific environment provided by Cornell University.