NF-κB Signaling is Required for X-Chromosome Inactivation Maintenance Following T cell Activation
X Chromosome Inactivation (XCI) is a female-specific process which balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment of Xist RNA and heterochromatic modifications on the inactive X chromosome (Xi), and these modifications become enriched at the Xi after cell stimulation. Here, we examined allele-specific gene expression and the epigenomic profiles of the Xi following T cell stimulation. We found that the Xi in unstimulated T cells is largely dosage compensated and is enriched with the repressive H3K27me3 modification, but not the H2AK119-ubiquitin (Ub) mark, even at promoters of XCI escape genes. Upon CD3/CD28-mediated T cell stimulation, the Xi accumulates H2AK119-Ub and H3K27me3 across the Xi. Next, we examined the T cell signaling pathways responsible for Xist RNA localization to the Xi and found that T cell receptor (TCR) engagement, specifically NF-κB signaling downstream of TCR, is required. Disruption of NF-κB signaling, using inhibitors or genetic deletions, in mice and patients with immunodeficiencies prevents Xist/XIST RNA accumulation at the Xi and alters expression of some X-linked genes. Our findings reveal a novel connection between NF-κB signaling pathways which impact XCI maintenance in female T cells.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2024 |
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Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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Enthalten in: |
bioRxiv : the preprint server for biology - (2024) vom: 12. Feb. |
Sprache: |
Englisch |
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Beteiligte Personen: |
Forsyth, Katherine S [VerfasserIn] |
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Anmerkungen: |
Date Revised 28.03.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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doi: |
10.1101/2024.02.08.579505 |
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funding: |
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PPN (Katalog-ID): |
NLM368958396 |
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520 | |a X Chromosome Inactivation (XCI) is a female-specific process which balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment of Xist RNA and heterochromatic modifications on the inactive X chromosome (Xi), and these modifications become enriched at the Xi after cell stimulation. Here, we examined allele-specific gene expression and the epigenomic profiles of the Xi following T cell stimulation. We found that the Xi in unstimulated T cells is largely dosage compensated and is enriched with the repressive H3K27me3 modification, but not the H2AK119-ubiquitin (Ub) mark, even at promoters of XCI escape genes. Upon CD3/CD28-mediated T cell stimulation, the Xi accumulates H2AK119-Ub and H3K27me3 across the Xi. Next, we examined the T cell signaling pathways responsible for Xist RNA localization to the Xi and found that T cell receptor (TCR) engagement, specifically NF-κB signaling downstream of TCR, is required. Disruption of NF-κB signaling, using inhibitors or genetic deletions, in mice and patients with immunodeficiencies prevents Xist/XIST RNA accumulation at the Xi and alters expression of some X-linked genes. Our findings reveal a novel connection between NF-κB signaling pathways which impact XCI maintenance in female T cells | ||
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700 | 1 | |a Toothacre, Natalie E |e verfasserin |4 aut | |
700 | 1 | |a Jiwrajka, Nikhil |e verfasserin |4 aut | |
700 | 1 | |a Driscoll, Amanda M |e verfasserin |4 aut | |
700 | 1 | |a Shallberg, Lindsey A |e verfasserin |4 aut | |
700 | 1 | |a Cunningham-Rundles, Charlotte |e verfasserin |4 aut | |
700 | 1 | |a Barmettler, Sara |e verfasserin |4 aut | |
700 | 1 | |a Farmer, Joceyln |e verfasserin |4 aut | |
700 | 1 | |a Verbsky, James |e verfasserin |4 aut | |
700 | 1 | |a Routes, John |e verfasserin |4 aut | |
700 | 1 | |a Beiting, Daniel P |e verfasserin |4 aut | |
700 | 1 | |a Romberg, Neil |e verfasserin |4 aut | |
700 | 1 | |a May, Michael J |e verfasserin |4 aut | |
700 | 1 | |a Anguera, Montserrat C |e verfasserin |4 aut | |
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