Single-nucleus multiomics reveals the gene-regulatory networks underlying sex determination of murine primordial germ cells
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ABSTRACT:
PROVIDER: PRJNA1216559 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32157829.fastq.gz | Fastqsanger.gz | |||
| SRR32157830_1.fastq.gz | Fastqsanger.gz | |||
| SRR32157830_2.fastq.gz | Fastqsanger.gz | |||
| SRR32157831_1.fastq.gz | Fastqsanger.gz | |||
| SRR32157831_2.fastq.gz | Fastqsanger.gz |
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Project description:Sex determination in the mammalian gonad involves coordinated lineage decisions in both germ cells and gonadal supporting cells. To define the regulatory programs driving these processes, we generated a single-nucleus multiomics atlas of murine fetal gonads, integrating chromatin accessibility and gene expression from individual nuclei across sex determination timepoints in both XX and XY gonads. In primordial germ cells (PGCs), joint RNA- and ATAC-seq profiling identified transcriptional states and regulatory elements underlying germ cell sex determination. These data resolved previously uncharacterized PGC subpopulations, revealed that changes in chromatin accessibility often precede transcriptional activation during PGC lineage commitment, and showed that sexual dimorphism in gene expression and chromatin state increases over developmental time. Motif enrichment and gene-regulatory network analyses highlighted distinct cohorts of transcription factors associated with XX and XY germ cell differentiation, including TFAP2C, TCFL5, GATA2, MGA, NR6A1, TBX4, and ZFX in XX PGCs, and forkhead-box and POU6 factors in XY PGCs. The dataset also captured dynamic signaling pathways (WNT, BMP, and RA) and potential cell-cell communication interactions between PGCs and the surrounding somatic niche. In the supporting cell lineage, integrated snRNA- and snATAC-seq analyses revealed how precursor cells diverge to form Sertoli cells in testes and granulosa cells in ovaries. Sex-specific chromatin accessibility in supporting cells emerged shortly after sex determination, accompanied by activation-associated histone marks. Motif analyses identified regulatory networks associated with ovary-enriched transcription factors such as LEF1 and MSX1, which promote granulosa fate by activating key target genes including Foxl2 and Fst (bioRxiv 2025.02.24.639877). Together, this dataset provides a multimodal reference map of the chromatin landscapes, transcriptional programs, and regulatory networks that coordinately govern sex determination of germ cells and supporting cells during murine gonadal development.
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Project description:Accurate specification of female and male germ cells during embryonic development is critical for sexual reproduction. Primordial germ cells (PGCs) are the bipotential precursors of mature gametes that commit to an oogenic or spermatogenic fate in response to sex-determining cues from the fetal gonad. The critical processes required for PGCs to integrate and respond to signals from the somatic environment in gonads are not understood. In this study, we developed the first single-nucleus multiomics map of chromatin accessibility and gene expression during murine PGC development in both XX and XY embryos. Profiling of cell-type specific transcriptomes and regions of open chromatin from the same cell captured the molecular signatures and gene networks underlying PGC sex determination. Joint RNA and ATAC data for single PGCs resolved previously unreported PGC subpopulations and cataloged a multimodal reference atlas of differentiating PGC clusters. We discovered that regulatory element accessibility precedes gene expression during PGC development, suggesting that changes in chromatin accessibility may prime PGC lineage commitment prior to differentiation. Similarly, we found that sexual dimorphism in chromatin accessibility and gene expression increased temporally in PGCs. Combining single-nucleus sequencing data, we computationally mapped the cohort of transcription factors that regulate the expression of sexually dimorphic genes in PGCs. For example, the gene regulatory networks of XX PGCs are enriched for the transcription factors, TFAP2c, TCFL5, GATA2, MGA, NR6A1, TBX4, and ZFX. Sex-specific enrichment of the forkhead-box and POU6 families of transcription factors was also observed in XY PGCs. Finally, we determined the temporal expression patterns of WNT, BMP, and RA signaling during PGC sex determination, and our discovery analyses identified potentially new cell communication pathways between supporting cells and PGCs. Our results illustrate the diversity of factors involved in programming PGCs towards a sex-specific fate.
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Project description:Accurate specification of female and male germ cells during embryonic development is critical for sexual reproduction. Primordial germ cells (PGCs) are the bipotential precursors of mature gametes that commit to an oogenic or spermatogenic fate in response to sex-determining cues from the fetal gonad. The critical processes required for PGCs to integrate and respond to signals from the somatic environment in gonads are not well understood. In this study, we developed the first single-nucleus multiomics map of chromatin accessibility and gene expression during murine PGC development in both XX and XY embryos. Profiling of cell-type-specific transcriptomes and regions of open chromatin from the same cell captured the molecular signatures and gene networks underlying PGC sex determination. Joint RNA and ATAC data for single PGCs resolved previously unreported PGC subpopulations and cataloged a multimodal reference atlas of differentiating PGC clusters. We discovered that regulatory element accessibility precedes gene expression during PGC development, suggesting that changes in chromatin accessibility may prime PGC lineage commitment prior to differentiation. Similarly, we found that sexual dimorphism in chromatin accessibility and gene expression increased temporally in PGCs. Combining single-nucleus sequencing data, we computationally mapped the cohort of transcription factors that regulate the expression of sexually dimorphic genes in PGCs. For example, the gene regulatory networks of XX PGCs are enriched for the transcription factors, TFAP2c, TCFL5, GATA2, MGA, NR6A1, TBX4, and ZFX. Sex-specific enrichment of the forkhead-box and POU6 families of transcription factors was also observed in XY PGCs. Finally, we determined the temporal expression patterns of WNT, BMP, and RA signaling during PGC sex determination, and our discovery analyses identified potentially new cell communication pathways between supporting cells and PGCs. Our results illustrate the diversity of factors involved in programming PGCs toward a sex-specific fate.
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Project description:The aim of the study was to identify differentially expressed genes during Gonadal Sex Determination in cattle. We performed a Rna-Seq analysis of XX and XY gonads during sex determination on embryonic days 35 (D35), 39 (D39) and 43 (D43). RNA-seq libraries were prepared from grouped gonads from D35, D39 and D43 males and females.
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Project description:Sex determination is the process by which and original bipotential gonad differentiate into either a testis or ovaries. While mammals and birds determine their sex solely by genetic clues (genetic sex determination, GSD), other vertebrates like the turtle Trachemys scripta are influenced by environmental factors, like temperature (environmental sex determination, ESD). In both cases an initially bipotential gonad develops into either testes or ovaries in response to GSD or ESD cues. In order to shed light into the differences and similarities between sex determination systems we performed single-cell RNA-seq on Trachemys scripta developing gonads during the sex determination window.
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Project description:single-cell chromatin accessibility profiling of mouse gonads during sex determination [scATAC-seq]
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Project description:Purpose: In this study we employed unbiased, genome-wide techniques to identify regulatory elements during murine sex determination. Methods: We performed ATAC-seq on 60K FACS-purified XX and XY gonadal cells before and after sex determination to map nucleosome depleted regions (NDRs) indicative of regulatory elements. To determine whether these are active enhancers, we performed ChIP-seq for H3K27ac, a histone modification that marks active enhancers in both sexes and time points. Transient transgenics was performed on select enhancers to determine whether they are functional in gonads during the sex determination stage. Results: We have produced a genome wide map of potential regulatory elements and active enhancers during the process of murine sex determination. Furthermore, we validated the power of our dataset by identifying a novel enhancer downstream of Bmp2, a female-specific gene. Conclusions: This work supplies a powerful resource for identifying chromatin regulatory elements active during mammalian sex determination.
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Project description:Avian sex is determined by various factors, such as the dosage of DMRT1 and cell-autonomous mechanisms. While the sex-determination mechanism in gonads is well analyzed, the mechanism in germ cells remains unclear. In this study, we explored the gene expression profiles of male and female primordial germ cells (PGCs) during embryogenesis in chickens to predict the mechanism of sex-determination. Male and female PGCs were isolated from blood and gonads with a purity > 96% using flow cytometry and analyzed using RNA-seq. Prior to settlement in the gonads, female circulating PGCs (cPGCs) obtained from blood displayed sex-biased expression. Gonadal PGCs (gPGCs) also displayed sex-biased expression, and the number of female-biased genes detected was higher than male-biased genes. The female-biased genes in gPGCs were enriched in some metabolic processes. To reveal the mechanisms underlying the transcriptional regulation of female-biased genes in gPGCs, we performed stimulation tests. Stimulation with retinoic acid against cultured gPGCs derived from male embryos resulted in the upregulation of several female-biased genes. Overall, our results suggest that sex determination of avian PGCs possess aspects of both cell-autonomous and somatic cell regulation. Moreover, it appears that sex determination occurs earlier in females than in males.
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