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Maintenance of X chromosome inactivation after T cell activation requires NF-κB signaling.

Authors :
Forsyth KS
Toothacre NE
Jiwrajka N
Driscoll AM
Shallberg LA
Cunningham-Rundles C
Barmettler S
Farmer J
Verbsky J
Routes J
Beiting DP
Romberg N
May MJ
Anguera MC
Source :
Science immunology [Sci Immunol] 2024 Oct 04; Vol. 9 (100), pp. eado0398. Date of Electronic Publication: 2024 Oct 04.
Publication Year :
2024

Abstract

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-κB signaling downstream of the TCR, was required for Xist RNA localization to the Xi. Disruption of NF-κB 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-κB signaling pathways, which affects XCI maintenance in T cells in females.

Details

Language :
English
ISSN :
2470-9468
Volume :
9
Issue :
100
Database :
MEDLINE
Journal :
Science immunology
Publication Type :
Academic Journal
Accession number :
39365876
Full Text :
https://doi.org/10.1126/sciimmunol.ado0398