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 了解哺乳动物生殖细胞生物学的最先进的基因组学技术。更确切地说，我们的 目标一直是了解遗传、表观遗传学和表观转录基础，以产生可存活的 健康配子，并探索这些事件的变化如何可能导致人类不孕。这很好 已知调节基因表达的各个方面所需的基因的破坏，包括染色质 修饰物，转录机制，和转录后调控通路的组成部分，导致 小鼠头部形态异常的精子形成，而男性精子数量增加 精子形态异常显著提高染色体非整倍体率、染色质致密率 与有生育能力的男性的精子相比，缺陷和改变的转录组图谱。因此，在此应用程序中，我们 试图了解基因表达的转录、转录后和转录外转录调控 染色质状态有助于单倍体生殖细胞分化为成熟精子。三 提出了项目，并提出了三个核心。项目I(丹科和科恩)将专注于 基因表达转录调控在减数分裂结束和进入减数分裂过程中的重要性 精子发生，重点是溴结构域蛋白，BRDT在促进转录方面的作用 关闭，从而允许适当的组蛋白到鱼精蛋白的替换和核致密。 项目II(Grimson，Schimenti，Hwang)将侧重于转录后基因的机制和功能 精子发生过程中mRNAs的处理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存在精子形态缺陷。项目III (Jaffrey)将探索N6-甲基腺苷(M6A)和N6，2‘-O-二甲基腺苷(M6Am)的动力学 小鼠和人类精子发生过程中对RNA的修饰及其重要性 在小鼠和人中产生健康精子的表型转录变化。这些研究将得到支持 由建立良好的行政核心(科恩)推动，将通过定期 会议、实习生活动、试点和种子基金，以及我们广受欢迎的“Tri-Repro”年度研讨会。我们的状态- -ART基因组创新核心(格勒尼尔)将作为一个创新中心，探索 生殖中的基因调控，专门从事一系列下一代测序技术，以支持 这些项目。最后，我们的外展核心(LIN)将为附近和传统的 服务不足，整个纽约州北部的学区，同时将我们的实习生和教职员工 将这些社区作为年轻的初出茅庐的科学家的榜样。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集成，以强大和明确的方式 机构支持，以及康奈尔大学提供的杰出科学环境。

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.