Regulatory mechanisms of meiotic entry and progression

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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.