Divergent regulatory element programs steer sex-specific supporting cell differentiation along mouse gonadal development [ATACseq]
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ABSTRACT:
PROVIDER: PRJNA1163275 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30734390_1.fastq.gz | Fastqsanger.gz | |||
| SRR30734390_2.fastq.gz | Fastqsanger.gz |
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Project description:Identifying cis-regulatory elements is essential for understanding how gene expression is precisely controlled during critical biological processes like sex determination. In this study, we aimed to uncover the cis-regulatory regions involved in the differentiation of supporting cells as Sertoli cells or pre-granulosa cells in the mouse gonads. To achieve this, we combined ATAC sequencing (ATAC-seq) and Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) of purified supporting cells at four developmental stages in both sexes. ATAC-seq enabled us to capture sexual and temporal changes in gene expression during cell differentiation, while ATAC-seq provided insight into chromatin accessibility, pinpointing regulatory regions that control these expression patterns. By integrating these two datasets, we identified specific cis-regulatory elements that likely guide the fate of supporting cells. Our findings shed light on the complex gene regulatory networks involved in sex fate differentiation, highlighting the critical role of cis-regulatory elements in orchestrating this process. These insights may also have implications for understanding disorders of sexual development (DSDs).
2025-06-01 | GSE277646 | GEO
Project description:Divergent regulatory element programs steer sex-specific supporting cell differentiation along mouse gonadal development [RNA-Seq]
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Project description:Identifying cis-regulatory elements is essential for understanding how gene expression is precisely controlled during critical biological processes like sex determination. In this study, we aimed to uncover the cis-regulatory regions involved in the differentiation of supporting cells as Sertoli cells or pre-granulosa cells in the mouse gonads. To achieve this, we combined RNA sequencing (RNA-seq) and Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) of purified supporting cells at four developmental stages in both sexes. RNA-seq enabled us to capture sexual and temporal changes in gene expression during cell differentiation, while ATAC-seq provided insight into chromatin accessibility, pinpointing regulatory regions that control these expression patterns. By integrating these two datasets, we identified specific cis-regulatory elements that likely guide the fate of supporting cells. Our findings shed light on the complex gene regulatory networks involved in sex fate differentiation, highlighting the critical role of cis-regulatory elements in orchestrating this process. These insights may also have implications for understanding disorders of sexual development (DSDs).
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Project description:Forkhead box L2 (FOXL2) is a forkhead box transcription factor expressed in the pituitary, ovaries, and eyelids. Human mutations in FOXL2 associate with the blepharophimosis, ptosis epicanthus and inversus syndrome (BPES), which can be linked to primary ovarian insufficiency, and are indirectly linked with differences of sex development (DSD). Animal studies have shown the crucial role that FOXL2 plays in the development, function, and maintenance of the ovary as well as in sex determination. However, the role of FOXL2 in early human somatic cell ovarian development is largely unknown. In this study, using CRISPR/Cas9 genome activation and a previously published in-house 14-day gonadal differentiation protocol, we show that FOXL2 downregulates coelomic epithelial markers GATA4 and LHX9, female gonadal markers RSPO1 and WNT4, and male gonadal markers SOX9 and NR0B1. Differentially expressed genes were mostly associated with Kyoto encyclopaedia of genes and genomes (KEGG) pathways relating to cell adhesion molecules and gene ontology (GO) pathways relating to extracellular matrix and junction formation. Moreover, comparative analysis with existing single cell RNA sequencing data from human in vivo-derived data elucidated that FOXL2 initiates downregulation of coelomic epithelial genes GATA4, LHX9 and UPK3B at day 6. At day 8, the genes ARX and GATA2 are transiently upregulated by FOXL2 induction and then downregulated as the genes LGR5, TSPAN8, OSR1 and TAC1 become upregulated. Thus, FOXL2 seems to support the exit of the differentiating cells from coelomic epithelium and first drives the cells towards a transitional identity and then into early supporting gonadal-like cells. The findings of this study will help largely in understanding normal gonadal development which can be used as a basis to elucidate pathological gonadal development underlying BPES.
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Project description:FOXL2 drives the differentiation of supporting gonadal cells in early ovarian development
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Project description:Gonadal supporting cells acquire sex-specific regulatory elements during mammalian sex determination
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Project description:Gonadal sex differentiation – testis versus ovary formation – is a fundamental process required for reproduction and evolution. Reflecting this importance, the embryonic gonads of vertebrate species comprise the same key cell types; germ cells, supporting cells and interstitial steroidogenic cells. Remarkably, the genetic triggers for gonadal sex differentiation vary across species (the SRY gene in mammals, DMRT1 in birds and some turtles, temperature in many reptiles, AMH and various other genes in fishes). Despite this variation, the cell biology of gonadal development was long thought to be largely conserved. Here, we present a comprehensive analysis of gonadal sex differentiation, using the chicken embryo as a model and considering the entire gonad. We sampled over 30,000 cells across several developmental stages, prior, during and after the onset of gonadal sex differentiation. The data provide several new insights into cell lineage specification during vertebrate gonadogenesis. Combining lineage tracing with single cell transcriptomics, the data show that somatic supporting cells of the embryonic chicken gonad do not derive from the coelomic epithelium, in contrast to other vertebrates studied. Instead, the early somatic precursors cells of the gonads in both sexes derive from a DMRT1+/PAX2+/WNT4+/OSR1+ mesenchymal cell population. In particular, PAX2 marks immigrating mesenchymal cells that give rise to the supporting cell lineage. We find a greater complexity of gonadal cell types than previously thought, including the identification of two distinct sub-populations of Sertoli cells in developing testes, and derivation of embryonic steroidogenic cells from a differentiated supporting cell lineage. We provide significantly improved resolution of gonadal cell types and identify several new gonadal marker genes. Altogether, these results indicate that, just as the genetic trigger for sex differs across vertebrate groups, cell lineage specification in the gonad may also vary substantially.
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Project description:We report the single nucleus multiome (RNAseq+ATACseq) of a female mouse pituitary sample. This dataset was generated for supporting the development of a data-driven batch inference method and transforms often heterogeneous data matrices obtained from different samples into a uniformly cell-type annotated and integrated dataset.
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Project description:The nuclear receptor subfamily 5 group A member 1 (NR5A1), encoding steroidogenic factor 1 (SF-1), has been identified as a critical factor in gonadal development in animal studies. A previous study of ours suggested that upregulation of NR5A1 during early gonadal differentiation in male (46,XY) human pluripotent stem cells steers the cells into a more mature gonadal cell type. However, the detailed role of NR5A1 in female gonadal differentiation has yet to be determined. In this study, by combining the processes of gonadal differentiation and conditional gene activation, we show that NR5A1 induction predominantly upregulates the female gonadal marker inhibin subunit α (INHA) and steroidogenic markers steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1), cytochrome P450 family 17 subfamily A member 1 (CYP17A1), hydroxy-delta-5-steroid dehydrogenase (HSD3B2) and hydroxysteroid 17-beta dehydrogenase 1 (HSD17B1). In contrast, NR5A1 induction did not seem to affect the bipotential gonadal markers gata binding protein 4 (GATA4) and Wilms tumour suppressor 1 (WT1) nor the female gonadal markers r-spondin 1 (RSPO1) and wnt family member 4 (WNT4). Differentially expressed genes were highly associated with adrenal and ovarian steroidogenesis pathways. Moreover, time-series analysis revealed different dynamic changes between male and female -induced samples, where continuously upregulated genes in female gonadal differentiation were mostly associated with adrenal steroidogenesis. Thus, in contrast to male gonadal differentiation, NR5A1 is necessary but not sufficient to steer human embryonic stem cell (hESC)-derived bipotential gonadal-like cells towards a more mature somatic, female cell fate. Instead, it seems to direct bipotential gonadal-like cells more towards a steroidogenic-like cell population. The information obtained in this study helps in elucidating the role of NR5A1 in gonadal differentiation of a female stem cell line.
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