Transcriptional progression during meiotic prophase I reveals sex-specific features and X chromosome dynamics in human fetal female germline.

Xueying Fan,Ioannis Moustakas,Roberto Matorras,Qijing Lei,Karoly Szuhai,Vanessa Torrens-Juaneda,Geert Hamer,Gonneke S K Pilgram,Susana M Chuva De Sousa Lopes,Cristina Eguizabal,Leoni A Louwe,Lucette Van Der Westerlaken,Hailiang Mei

doi:10.1371/journal.pgen.1009773

Abstract

During gametogenesis in mammals, meiosis ensures the production of haploid gametes. The timing and length of meiosis to produce female and male gametes differ considerably. In contrast to males, meiotic prophase I in females initiates during development. Hence, the knowledge regarding progression through meiotic prophase I is mainly focused on human male spermatogenesis and female oocyte maturation during adulthood. Therefore, it remains unclear how the different stages of meiotic prophase I between human oogenesis and spermatogenesis compare. Analysis of single-cell transcriptomics data from human fetal germ cells (FGC) allowed us to identify the molecular signatures of female meiotic prophase I stages leptotene, zygotene, pachytene and diplotene. We have compared those between male and female germ cells in similar stages of meiotic prophase I and revealed conserved and specific features between sexes. We identified not only key players involved in the process of meiosis, but also highlighted the molecular components that could be responsible for changes in cellular morphology that occur during this developmental period, when the female FGC acquire their typical (sex-specific) oocyte shape as well as sex-differences in the regulation of DNA methylation. Analysis of X-linked expression between sexes during meiotic prophase I suggested a transient X-linked enrichment during female pachytene, that contrasts with the meiotic sex chromosome inactivation in males. Our study of the events that take place during meiotic prophase I provide a better understanding not only of female meiosis during development, but also highlights biomarkers that can be used to study infertility and offers insights in germline sex dimorphism in humans.

Highlights

Meiosis is a particular cell division that aims to produce fully functional haploid gametes, necessary for the formation of a diploid zygote after fertilization [1]
We have analysed single-cell RNA sequencing data of human germ cells and identified the molecular signatures associated with progression through the different stages of the female meiotic prophase I
We observed that many genes differentially expressed during different female meiotic prophase I stages are related to male fertility

Summary

Introduction

Meiosis is a particular cell division that aims to produce fully functional haploid gametes, necessary for the formation of a diploid zygote after fertilization [1]. Unlike male germ cells that enter meiosis only during puberty and complete the whole process within a period of two months (about 74 days in humans), female meiosis initiates during fetal development but only completes after fertilization, decades later. In contrast to mouse that shows a transient rostrocaudal wave during meiotic entry [2,3], human female fetal germ cell (FGC) development is strongly asynchronous during the second trimester [4,5,6]. By 18 weeks post-fertilization (WPF), corresponding to 20 weeks of gestation, distinct cellular states, showing characteristic morphology and expressing specific markers, are present in different compartments of the ovary, that is the outer cortex, germinal cords and inner cortex [5,7,8]. The most peripheral germ cells, under the germinative epithelium, retain expression of pluripotency markers, such as POU5F1 (or OCT4) and NANOG [7,8]

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Conclusion