| First Author | Forsyth KS | Year | 2024 |
| Journal | Sci Immunol | Volume | 9 |
| Issue | 100 | Pages | eado0398 |
| PubMed ID | 39365876 | Mgi Jnum | J:360904 |
| Mgi Id | MGI:7782827 | Doi | 10.1126/sciimmunol.ado0398 |
| Citation | Forsyth KS, et al. (2024) Maintenance of X chromosome inactivation after T cell activation requires NF-kappaB signaling. Sci Immunol 9(100):eado0398 |
| abstractText | X chromosome inactivation (XCI) balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment of X-inactive specific transcript (Xist) RNA and heterochromatic modifications on the inactive X chromosome (Xi), which are involved in maintenance of XCI, and these modifications return to the Xi after stimulation. Here, we examined allele-specific gene expression and epigenomic profiles of the Xi in T cells. We found that the Xi in unstimulated T cells is largely dosage compensated and enriched with the repressive H3K27me3 modification but not the H2AK119-ubiquitin (Ub) mark. Upon T cell stimulation mediated by both CD3 and CD28, the Xi accumulated H2AK119-Ub at gene regions of previous H3K27me3 enrichment. T cell receptor (TCR) engagement, specifically NF-kappaB signaling downstream of the TCR, was required for Xist RNA localization to the Xi. Disruption of NF-kappaB signaling in mouse and human T cells using genetic deletion, chemical inhibitors, and patients with immunodeficiencies prevented Xist/XIST RNA accumulation at the Xi and altered X-linked gene expression. Our findings reveal a previously undescribed connection between NF-kappaB signaling pathways, which affects XCI maintenance in T cells in females. |
