Natalie E Toothacre, Kiara L Rodríguez-Acevedo, Keenan J Wiggins, Christopher D Scharer, Montserrat C Anguera. Xist RNA dependent and independent mechanisms regulate dynamic X chromosome inactivation in B lymphocytes. Cell Rep. 2026 Apr 9;45(4):117254. doi: 10.1016/j.celrep.2026.117254. Epub ahead of print. PMID: 41964951; PMCID: PMC13142736.

Abstract

X chromosome inactivation (XCI) equalizes X-linked gene expression between the sexes through heterochromatic mark accumulation. XCI is dynamic in female B cells, as cytological enrichment of Xist RNA and heterochromatic marks on the inactive X chromosome (Xi) are absent in naive B cells yet return following stimulation. Here, we asked whether heterochromatic histone marks are present on the Xi in naive B cells and whether Xist RNA is required for their deposition and retention following stimulation. We find that the Xi in naive B cells is depleted for H2AK119Ub and H3K9me3 but enriched for DNA methylation and H3K27me3, which maintain an Xist RNA-dependent memory of XCI. Upon stimulation, Xist-independent H3K27me3 and Xist-dependent H2AK119Ub modifications accumulate across the Xi with temporal and spatial specificity. Our findings reveal the importance of Xist RNA, H3K27me3, and H2AK119Ub marks for Xi gene regulation following female B cell stimulation.