Species-specific regulation of XIST by the JPX/FTX orthologs
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA824048 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18661598_1.fastq.gz | Fastqsanger.gz | |||
| SRR18661598_2.fastq.gz | Fastqsanger.gz | |||
| SRR18661599_1.fastq.gz | Fastqsanger.gz | |||
| SRR18661599_2.fastq.gz | Fastqsanger.gz |
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Project description:X chromosome inactivation (XCI) is a developmental regulatory process that initiates with remarkable diversity in various mammalian species. Here we addressed the contribution of XCI regulators, most of which are lncRNA genes (LRGs) characterized in the mouse, to this mechanistic diversity. By combining analysis of single-cell RNA-seq data from early human embryogenesis with various functional assays in pluripotent stem- and differentiated cells, we demonstrate that the function of Ftx is not conserved, while JPX stands a major regulator of XIST expression in human and in mouse. However, the underlying mechanisms differ radically between species and require Jpx RNA in the mouse and the act of transcription of the JPX locus in the human. Moreover, biogenesis of XIST is affected at different regulatory steps between these species. This study illustrates how diversification of LRG modus operanti during evolution provide opportunities for innovations within constrained gene regulatory networks.
2023-02-01 | GSE200317 | GEO
Project description:X chromosome inactivation (XCI) is an essential process, yet it initiates with remarkable diversity in various mammalian species. XIST, the main trigger of XCI, is controlled in the mouse by an interplay of lncRNA genes (LRGs), some of which evolved concomitantly to XIST and have orthologues across all placental mammals. Here, we addressed the functional conservation of human orthologues of two such LRGs, FTX and JPX. By combining analysis of single-cell RNA-seq data from early human embryogenesis with various functional assays in matched human and mouse pluripotent stem- or differentiated post-XCI cells, we demonstrate major functional differences for these orthologues between species, independently of primary sequence conservation. While the function of FTX is not conserved in humans, JPX stands as a major regulator of XIST expression in both species. However, we show that different entities of JPX control the production of XIST at various steps depending on the species. Altogether, our study highlights the functional versatility of LRGs across evolution, and reveals that functional conservation of orthologous LRGs may involve diversified mechanisms of action. These findings represent a striking example of how the evolvability of LRGs can provide adaptative flexibility to constrained gene regulatory networks.
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Project description:Known to regulate chromosome looping on a genome-wide scale, the noncoding Jpx RNA was originally shown to control X-chromosome counting and induce Xist expression during X-chromosome inactivation (XCI). Not fully understood is how Jpx upregulates Xist in coordination with Tsix downregulation in cis. Here, by integrating epigenomic data and polymer modeling in a mouse embryonic stem cell model, we demonstrate that Jpx controls architectural and transcriptional dynamics within anti- and pro-XCI zones of the X-inactivation center. Distinct topological changes occur on the future active (Xa) and inactive (Xi) chromosomes. Jpx binds the enhancer of Tsix on the future Xi and alters loop formation to favor Xist induction, coordinately releasing CTCF from Tsix and Xist in cis on the future Xi. Thus, by controlling a dynamic rewiring of functional loops, Jpx flips a transcriptional switch to control mutually exclusive Tsix and Xist expression in cis.
2025-06-11 | GSE283642 | GEO
Project description:Known to regulate chromosome looping on a genome-wide scale, the noncoding Jpx RNA was originally shown to control X-chromosome counting and induce Xist expression during X-chromosome inactivation (XCI). Not fully understood is how Jpx upregulates Xist in coordination with Tsix downregulation in cis. Here, by integrating epigenomic data and polymer modeling in a mouse embryonic stem cell model, we demonstrate that Jpx controls architectural and transcriptional dynamics within anti- and pro-XCI zones of the X-inactivation center. Distinct topological changes occur on the future active (Xa) and inactive (Xi) chromosomes. Jpx binds the enhancer of Tsix on the future Xi and alters loop formation to favor Xist induction, coordinately releasing CTCF from Tsix and Xist in cis on the future Xi. Thus, by controlling a dynamic rewiring of functional loops, Jpx flips a transcriptional switch to control mutually exclusive Tsix and Xist expression in cis.
2025-06-11 | GSE283641 | GEO
Project description:Known to regulate chromosome looping on a genome-wide scale, the noncoding Jpx RNA was originally shown to control X-chromosome counting and induce Xist expression during X-chromosome inactivation (XCI). Not fully understood is how Jpx upregulates Xist in coordination with Tsix downregulation in cis. Here, by integrating epigenomic data and polymer modeling in a mouse embryonic stem cell model, we demonstrate that Jpx controls architectural and transcriptional dynamics within anti- and pro-XCI zones of the X-inactivation center. Distinct topological changes occur on the future active (Xa) and inactive (Xi) chromosomes. Jpx binds the enhancer of Tsix on the future Xi and alters loop formation to favor Xist induction, coordinately releasing CTCF from Tsix and Xist in cis on the future Xi. Thus, by controlling a dynamic rewiring of functional loops, Jpx flips a transcriptional switch to control mutually exclusive Tsix and Xist expression in cis.
2025-06-11 | GSE225226 | GEO
Project description:In this project, we have studied the role of Chd8 in Xist regulation and XCI initiation by means of Chd8 Knock-Downs (KD) and Knock-Out (KO).
2021-09-10 | PXD024155 | Pride
Project description:Jpx RNA controls Xist induction through spatial reorganization of the mouse X-inactivation center
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Project description:Chromosome loops shift dynamically during development, homeostasis, and disease. CTCF is known to anchor loops and construct 3D genomes, but how anchor sites are selected is not yet understood. Here we unveil Jpx RNA as a determinant of anchor selectivity. Jpx RNA targets thousands of genomic sites, preferentially binding promoters of active genes. Depleting Jpx RNA causes ectopic CTCF binding, massive shifts in chromosome looping, and downregulation of >700 Jpx target genes. Without Jpx, thousands of lost loops are replaced by de novo loops anchored by ectopic CTCF sites. Although Jpx controls CTCF binding on a genome-wide basis, it acts selectively at the subset of developmentally sensitive CTCF sites. Specifically, Jpx targets low-affinity CTCF motifs and displaces CTCF protein through competitive inhibition. We conclude that Jpx acts as a CTCF release factor and shapes the 3D genome by regulating anchor site usage.
2021-12-01 | GSE144056 | GEO
Project description:In mammals, dosage compensation between XX and XY individuals occurs through X chromosome inactivation (XCI). The noncoding Xist RNA is expressed and initiates XCI only when more than one X chromosome is present. Current models invoke a dependency on the X-to-autosome ratio (X:A), but molecular factors remain poorly defined. Here, we demonstrate that molecular titration between an X-encoded RNA and an autosomally encoded protein dictates Xist induction. In pre-XCI cells, CTCF protein represses Xist transcription. At the onset of XCI, Jpx RNA is upregulated, binds CTCF, and extricates CTCF from one Xist allele. We demonstrate that CTCF is an RNA-binding protein and is titrated away from the Xist promoter by Jpx RNA. Thus, Jpx activates Xist by evicting CTCF. The functional antagonism via molecular titration reveals a role for long noncoding RNA in epigenetic regulation.
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Project description:Jpx RNA controls Xist induction through spatial reorganization of the mouse X-inactivation center [RNA-Seq]
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