Single-cell RNA-seq identified novel genes involved in primordial follicle formation.
Single-cell RNA-seq identified novel genes involved in primordial follicle formation.
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DOI：
10.3389/fendo.2023.1285667
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发表时间：
2023
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
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哺乳动物的原始卵泡（PFs）数量决定了卵巢的储备能力，原始卵泡形成（PFF）受损会导致卵巢功能不全（POI）。通过分析小鼠和人类卵巢PFF过程中进行的公共单细胞RNA测序，我们发现了PFF过程中新的功能基因和新的配体-受体相互作用。通过免疫荧光和体外卵巢培养，我们确定了PFF中基因和配体受体相互作用的机制。我们还对93例POI患者进行了全外显子组测序（WES），并对465例对照患者进行了全基因组测序（WGS）。通过计算机分析和功能验证进一步研究POI患者的变异。我们发现生殖细胞中的ANXA7（膜联蛋白A7）和GTF2F1（一般转录因子IIF亚基1）可能是促进PFF的新基因。生殖细胞中的配体Mdk （midkine）和颗粒细胞中的受体Sdc1 （syndecan 1）是一种新的相互作用，对PFF至关重要。基于免疫荧光，我们证实PFs中ANXA7与种系囊肿相比显著上调，并且在PFF期间，GTF2F1、MDK和SDC1在25周的人胎儿卵巢中均匀表达。体外研究表明，Anxa7和Gtf2f1分别通过调控Jak/Stat3和Jnk信号通路对小鼠PFF至关重要。配体受体（Mdk-Sdc1）通过调节Pi3k-akt信号通路对PFF至关重要。在病例中发现了GTF2F1的两个杂合变异体和SDC1的一个杂合变异体，而在对照组中未发现变异体。POI病例中GTF2F1或SDC1蛋白水平明显低于对照组，说明这两种基因对卵巢功能的致病作用具有剂量依赖性。我们的研究在PFF过程中发现了新的基因和新的配体-受体相互作用，并进一步扩展了POI的遗传结构。
The number of primordial follicles (PFs) in mammals determines the ovarian reserve, and impairment of primordial follicle formation (PFF) will cause premature ovarian insufficiency (POI). By analyzing public single-cell RNA sequencing performed during PFF on mice and human ovaries, we identified novel functional genes and novel ligand-receptor interaction during PFF. Based on immunofluorescence and in vitro ovarian culture, we confirmed mechanisms of genes and ligand-receptor interaction in PFF. We also applied whole exome sequencing (WES) in 93 cases with POI and whole genome sequencing (WGS) in 465 controls. Variants in POI patients were further investigated by in silico analysis and functional verification. We revealed ANXA7 (annexin A7) and GTF2F1 (general transcription factor IIF subunit 1) in germ cells to be novel potentially genes in promoting PFF. Ligand Mdk (midkine) in germ cells and its receptor Sdc1 (syndecan 1) in granulosa cells are novel interaction crucial for PFF. Based on immunofluorescence, we confirmed significant up-regulation of ANXA7 in PFs compared with germline cysts, and uniform expression of GTF2F1, MDK and SDC1 during PFF, in 25 weeks human fetal ovary. In vitro investigation indicated that Anxa7 and Gtf2f1 are vital for mice PFF by regulating Jak/Stat3 and Jnk signaling pathways, respectively. Ligand-receptor (Mdk-Sdc1) are crucial for PFF by regulating Pi3k-akt signaling pathway. Two heterozygous variants in GTF2F1, and one heterozygous variants in SDC1 were identified in cases, but no variant were identified in controls. The protein level of GTF2F1 or SDC1 in POI cases are significantly lower than that of controls, indicating the pathogenic effects of the two genes on ovarian function were dosage dependent. Our study identified novel genes and novel ligand-receptor interaction during PFF, and further expanding the genetic architecture of POI.
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