NF-κB Signaling is Required for X-Chromosome Inactivation Maintenance Following T cell Activation
ABSTRACT X Chromosome Inactivation (XCI) is a female-specific process which balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment ofXistRNA 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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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 14. Feb. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Forsyth, Katherine S. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.02.08.579505 |
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| PPN (Katalog-ID): |
XBI042484278 |
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| 100 | 1 | |a Forsyth, Katherine S. |e verfasserin |0 (orcid)0000-0002-4991-1601 |4 aut | |
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| 520 | |a ABSTRACT X Chromosome Inactivation (XCI) is a female-specific process which balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment ofXistRNA 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. |4 aut | |
| 700 | 1 | |a Jiwrajka, Nikhil |4 aut | |
| 700 | 1 | |a Driscoll, Amanda M. |4 aut | |
| 700 | 1 | |a Shallberg, Lindsey A. |4 aut | |
| 700 | 1 | |a Cunningham-Rundles, Charlotte |4 aut | |
| 700 | 1 | |a Barmettler, Sara |4 aut | |
| 700 | 1 | |a Farmer, Joceyln |0 (orcid)0000-0003-4901-9848 |4 aut | |
| 700 | 1 | |a Verbsky, James |4 aut | |
| 700 | 1 | |a Routes, John |4 aut | |
| 700 | 1 | |a Beiting, Daniel P. |4 aut | |
| 700 | 1 | |a Romberg, Neil |4 aut | |
| 700 | 1 | |a May, Michael J. |4 aut | |
| 700 | 1 | |a Anguera, Montserrat C. |0 (orcid)0000-0003-4992-3079 |4 aut | |
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