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Xist RNA regulates remodeling of the Xi during B cell stimulation [RNA-seq]

ABSTRACT: The inactive X (Xi) is formed by a process called X-Chromosome Inactivation (XCI), with Xist upregulation, retention of Xist RNA transcripts at the Xi, chromatin re-organization, and transcriptional silencing. Female lymphocytes have ‘dynamic’ XCI maintenance where Xist RNA is transcribed but absent from the Xi in naïve lymphocytes and re-localizes after in-vitro activation. How ‘dynamic’ XCI impacts Xi dosage and nuclear organization, or where Xist RNA interacts with the Xi is unknown. Here we find maintenance of Xi dosage and global structure despite the absence of Xist RNA in naïve B-cells. However, we identified 104 escape genes and observe a gain of de-novo TADs on the Xi. Stimulation-dependent Xi remodeling co-occurs with Xist RNA re-accumulation at the Xi, and loss of Xist increases TAD remodeling and decompacts the Xi in both naïve and stimulated B-cells. Altogether, these results reveal B-cell specific Xi plasticity which could underlie female-specific mechanisms in lymphocytes.

ORGANISM(S): Mus musculus Mus

PROVIDER: GSE208393 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:In naïve human pluripotent stem cells (hPSCs) that represent the pre-implantation embryonic states, epigenetic regulators for cell identity remain poorly defined. One of the major remaining questions in naïve stem cell biology is how female cells mediate and regulate X chromosome inactivation (XCI). Recent studies incorporating single-cell RNA sequencing (scRNA-seq) have demonstrated that transcript-based technologies are insufficient to unequivocally resolve XCI regulation in a human system. Instead, 3D genomics shows immense promise for studying XCI by interrogating changes to the X chromosomes’ 3D states. Here, we sought to characterize the 3D state of the X chromosome in naïve and primed hPSCs. Using chromatin tracing, we analyzed the folding conformations of whole X chromosomes with megabase genomic resolution in multiple naïve and primed hPSC lines. Our data found that X chromosomes in female naive hPSCs exhibit a range of spatial folding conformations similar to the active X chromosome (Xa) and the inactive X chromosome (Xi) in somatic cells; these data suggest that naïve hPSCs have initiated XCI. As XCI process ultimately generates detectable differences in volume between the Xa and the Xi, we measured the radius of gyration of individual X chromosome copies across various hPSC cell lines and culture conditions. In naïve hPSCs, our results show that the X chromosomes with Xi-like conformations are not more compact than those with Xa-like conformation. This finding is directly counter to the Xi compaction typically observed in post-XCI female somatic cells. These contradictory 3D signatures of XCI suggest that female naïve hPSCs have initiated the XCI process, but are poised before XCI-driven silencing in a metastable state. As observed in H7 naïve hPSCs, this metastable state can be abolished through classically noted means, such as the loss of Xp chromatin, leading to the deleted p X chromosome (dXp). The Xp loss observed here seems to drive XIST expression and accumulation around the dXp chromosome. Overall, our findings provide insight into the previously undefined X chromosome status in naïve hPSCs in single chromosome resolution, and are critical in understanding the unique epigenetic regulation in early embryonic cells.

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Xist RNA regulates remodeling of the Xi during B cell stimulation [RNA-seq]

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