Single-cell RNA-Seq reveals a highly coordinated transcriptional program in mouse germ cells during primordial follicle formation.
Single-cell RNA-Seq reveals a highly coordinated transcriptional program in mouse germ cells during primordial follicle formation.
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作者：
He Y;Chen Q;Dai J;Cui Y;Zhang C;Wen X;Li J;Xiao Y;Peng X;Liu M;Shen B;Sha J;Hu Z;Li J;Shu W
哺乳动物原始卵泡的组装是卵巢生物学中最关键的过程之一。它直接影响雌性在整个生殖期内可利用的卵母细胞数量。原始卵泡的过早耗竭会导致卵巢疾病——原发性卵巢功能不全（POI）。为了描绘这一过程中卵母细胞的发育轨迹和调控机制，我们对新生（P0.5）小鼠卵巢中的单个生殖细胞进行了RNA测序。划分出了三个细胞簇，它们分别对应新生卵巢中的三种细胞状态（生殖细胞囊、囊破裂和卵泡）。通过Monocle分析，构建了卵母细胞发育的统一轨迹，一系列基因沿伪时间轴呈现动态变化。基因本体论（Gene Ontology）术语富集分析显示，减数分裂相关基因显著减少，而卵母细胞特异性基因急剧增加，这标志着生殖细胞向功能性卵母细胞的转变。随后，我们利用单细胞调控网络推理和聚类（SCENIC）算法建立了调控子网络，并确定了在卵泡形成过程中可能维持转录程序的候选转录因子。后续功能研究通过使用siRNA敲低和基因修饰小鼠模型，进一步揭示了已鉴定的调控子Id2及其家族成员Id1对原始卵泡库建立的差异调控。总之，我们的研究系统地重建了卵母细胞中的分子级联反应，并确定了一系列与卵泡形成和发育相关的基因和分子通路。
原始卵泡的组装决定了雌性在整个生殖期内可利用的卵母细胞数量。原始卵泡的过早耗竭会导致卵巢疾病——原发性卵巢功能不全。我们对新生小鼠卵巢中的单个生殖细胞进行了RNA测序，数据显示随着生殖细胞向功能性卵母细胞的转变，基因表达呈现动态变化。我们的研究突出了转录调控在这一过程中的重要性。
The assembly of primordial follicles in mammals represents one of the most critical processes in ovarian biology. It directly affects the number of oocytes available to a female throughout her reproductive life. Premature depletion of primordial follicles contributes to the ovarian pathology primary ovarian insufficiency (POI). To delineate the developmental trajectory and regulatory mechanisms of oocytes during the process, we performed RNA‐seq on single germ cells from newborn (P0.5) ovaries. Three cell clusters were classified which corresponded to three cell states (germ cell cyst, cyst breakdown, and follicle) in the newborn ovary. By Monocle analysis, a uniform trajectory of oocyte development was built with a series of genes showed dynamic changes along the pseudo‐timeline. Gene Ontology term enrichment revealed a significant decrease in meiosis‐related genes and a dramatic increase in oocyte‐specific genes which marked the transition from a germ cell to a functional oocyte. We then established a network of regulons by using single‐cell regulatory network inference and clustering (SCENIC) algorithm and identified possible candidate transcription factors that may maintain transcription programs during follicle formation. Following functional studies further revealed the differential regulation of the identified regulon Id2 and its family member Id1, on the establishment of primordial follicle pool by using siRNA knockdown and genetic modified mouse models. In summary, our study systematically reconstructed molecular cascades in oocytes and identified a series of genes and molecular pathways in follicle formation and development. The assembly of primordial follicle determines the number of oocytes available to a female throughout her reproductive life. Premature depletion of primordial follicles contributes to the ovarian pathology primary ovarian insufficiency. We performed RNA‐seq on single germ cells from newborn mouse ovary and the data revealed dynamic gene expressions along with the transition of germ cells to a functional oocyte. Our study highlights the importance of transcriptional regulations on the process.
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