X chromosome inactivation (XCI) occurs in female mammals to normalize gene expression of sex chromosomes. This process is known to involve cis-mediated interactions by the long-noncoding RNA Xist on the inactive X (Xi) chromosome. This process is often incomplete with some genes that escape XCI (such as Xist) and many immune-relevant genes are expressed on the X chromosome, which might contribute to sex biases in autoimmune diseases and immune responses. In Science Immunology, Forsyth et al. use a clever mouse F₁ hybrid model to study allele-specific Xi chromosome inactivation in resting and activated T cells. They find that Xi chromosomes in unstimulated T cells are enriched for the repressive H3K27me3 epigenetic modification but less so for the repressive chromatin mark H2AK119-ubiquitin (Ub). Upon T cell stimulation, specifically signaling via the T cell receptor, Xi accumulates H2AK119-Ub modifications and co-localization with Xist. The authors show that NF-κB signaling, but not Ca²⁺-NFAT signaling, is required for localization of Xist to the Xi chromosome; however, Xist expression does not change after NF-κB inhibition. Notably, the expression of the XCI escape genes in unstimulated and stimulated T cells largely overlaps. These intriguing findings prompt many questions about what controls Xist localization to the Xi chromosome and what NF-κB-dependent genes direct this process. Moreover, how does XCI in T cells influence TCR repertoires, epigenetic memory and subsequent effector functions.

Original reference: Sci. Immunol. 9, eado0398 (2024)

X 染色体失活 （XCI） 发生在雌性哺乳动物中，以使性染色体的基因表达正常化。已知该过程涉及非活性 X （习） 染色体上长链非编码 RNA Xist 的顺式介导的相互作用。这个过程通常是不完整的，一些逃避 XCI 的基因（如 Xist）和许多免疫相关基因在 X 染色体上表达，这可能导致自身免疫性疾病和免疫反应中的性别偏倚。在《科学免疫学》中，Forsyth 等人使用聪明的小鼠 F₁ 杂交模型来研究静息和活化 T 细胞中等位基因特异性 习 染色体失活。他们发现，未受刺激的 T 细胞中的 习 染色体因抑制性 H3K27me3 表观遗传修饰而富集，但对抑制性染色质标记 H2AK119-泛素 （Ub） 的富集程度较低。在 T 细胞刺激后，特别是通过 T 细胞受体进行信号传导，习积累 H2AK119-Ub 修饰并与 Xist 共定位。作者表明，NF-κB 信号传导，而不是 Ca²⁺-NFAT 信号传导，是 Xist 定位到 习 染色体所必需的;然而，Xist 表达在 NF-κB 抑制后没有变化。值得注意的是，XCI 逃逸基因在未刺激和受刺激的 T 细胞中的表达在很大程度上重叠。这些有趣的发现引发了许多问题，即是什么控制了 Xist 定位到 习 染色体以及哪些 NF-κB 依赖性基因指导了这一过程。此外，T 细胞中的 XCI 如何影响 TCR 库、表观遗传记忆和随后的效应器功能。

原始参考文献：Sci. Immunol.9、EADO0398 （2024）