NF-κB Signaling is Required for X-Chromosome Inactivation Maintenance Following T cell Activation. bioRxiv 2024 Feb 12
Date
02/26/2024Pubmed ID
38405871Pubmed Central ID
PMC10888971DOI
10.1101/2024.02.08.579505Abstract
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.
Author List
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 MCAuthors
John M. Routes MD Chief, Professor in the Pediatrics department at Medical College of WisconsinJames Verbsky MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
