Regulatory mechanisms of meiotic entry and progression

摘要 减数分裂是二倍体细胞产生单倍体配子细胞的过程，是有性生殖所必需的。 繁殖。这种保守的细胞分裂程序是由一个专门的转录组驱动的，它支持 复杂的染色体行为与细胞周期进程相结合。减数分裂中的染色体错误 行为是非整倍体的主要原因，因此也是人类流产和出生异常的主要原因。我的研究 该计划旨在了解减数分裂的遗传和分子机制，以及 调节生殖系中的基因表达和染色体行为。我们用鼠标来探索这些关键的 细胞生物学的各个方面。我们目前的研究主要集中在调节减数分裂的两条途径上，一个细胞- 自治的和一个非小区自治的，概述如下： ·从有丝分裂到减数分裂的转换是一个关键的细胞命运转变，涉及完全重塑 转录组，但对哺乳动物中调节这种变化的机制知之甚少。我们最近的工作 确定了一条控制有丝分裂到减数分裂开关的重要途径。在这个途径中，RNA解旋酶 YTHDC2与其结合伙伴MEIOC一起，通过直接转录后调控基因表达 与RNA靶标的相互作用。然而，这一规定是如何实现的仍不清楚。强有力的方法 为了绘制全基因组蛋白质-RNA相互作用图和创新的结构-功能突变体 为了定义这种机制如何控制基因表达，它如何识别和接触RNA，以及它如何 与其他细胞机制相交，以调节减数分裂进程。 ·后生动物细胞在合胞体中进行减数分裂，在细胞之间共享细胞质和RNA。这是一个 减数分裂的基本特征，如通过基因消融细胞间桥而破坏细胞质共享 连接减数分裂细胞会导致雄性小鼠减数分裂失败和不育。然而，潜在的功能 通过细胞间桥实现细胞质共享的意义还知之甚少。最新进展通知 关于细胞质共享在调控基因表达和减数分裂染色体中作用的假说 动力学。我们将利用显微镜和单细胞基因组学的进步来测试这些并确定 这种引人注目的、进化上保守的减数分裂特征的作用。

ABSTRACT Meiosis is the process by which a diploid cell gives rise to haploid gamete cells and is essential for sexual reproduction. This conserved cell division program is driven by a specialized transcriptome, which supports complex chromosome behaviors that are integrated with cell cycle progression. Errors in meiotic chromosome behaviors are a major cause of aneuploidy, and thus of miscarriage and birth anomalies in humans. My research program aims to understand the genetic and molecular mechanisms of meiosis, and of the processes that regulate gene expression and chromosome behaviors in the germline. We use mouse to explore these critical aspects of cell biology. Our current research primarily focuses on two pathways that regulate meiosis, one cell- autonomous and one non-cell-autonomous, as outlined below: · The switch from mitosis to meiosis is a critical cell fate transition that involves complete remodeling of the transcriptome, but little is known about the mechanisms regulating this change in mammals. Our recent work identified an essential pathway that controls the mitosis-to-meiosis switch. In this pathway, the RNA helicase YTHDC2, along with its binding partner MEIOC, regulates gene expression post-transcriptionally via direct interaction with RNA targets. How this regulation is accomplished remains unclear, however. Powerful methods for mapping genome-wide protein-RNA interactions and innovative structure-function mutants will be exploited to define how this machinery controls gene expression, how it recognizes and engages RNA, and how it intersects with other cellular machinery to regulate meiotic progression. · Metazoan cells undergo meiosis in a syncytium, sharing cytoplasm and RNA between cells. This is an essential feature of meiosis, as disruption of cytoplasmic sharing by genetic ablation of the intercellular bridges connecting meiotic cells leads to meiotic failure and infertility in male mice. However, the underlying functional significance of cytoplasmic sharing via intercellular bridges is poorly understood. Recent advances inform hypotheses about the roles of cytoplasmic sharing in regulating gene expression and meiotic chromosome dynamics. We will leverage advances in microscopy and single-cell genomics to test these and to determine the roles of this striking, evolutionarily conserved meiotic feature.