Toothacre Natalie E, Rodríguez-Acevedo Kiara L, Wiggins Keenan J, Scharer Christopher D, Anguera Montserrat C
bioRxiv. 2025 Jan 29:2025.01.27.635124. doi: 10.1101/2025.01.27.635124.
X-Chromosome Inactivation (XCI) involves epigenetic pathways to equalize X-linked gene expression between female and male mammals. 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 naïve B cells yet return following mitogenic stimulation. Here, we asked whether any heterochromatic histone marks are present on the Xi in naïve B cells, and whether Xist RNA is required for their deposition and retention following stimulation. We find that the Xi in naïve B cells is depleted for H2AK119Ub and H3K9me3 but enriched for DNA methylation and H3K27me3, which maintain an Xist RNA-dependent epigenetic 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 the epigenetic integrity of X-linked genes across the Xi following female B cell stimulation.
X染色体失活（XCI）涉及表观遗传途径，以使雌性和雄性哺乳动物之间的X连锁基因表达均等。XCI在雌性B细胞中是动态的，因为在未活化的B细胞中，Xist RNA和失活X染色体（Xi）上的异染色质标记在细胞学上并不富集，但在有丝分裂原刺激后会恢复。在这里，我们研究了未活化的B细胞中Xi上是否存在任何异染色质组蛋白标记，以及刺激后它们的沉积和保留是否需要Xist RNA。我们发现，未活化的B细胞中的Xi缺乏H2AK119Ub和H3K9me3，但富含DNA甲基化和H3K27me3，它们维持了XCI的Xist RNA依赖性表观遗传记忆。受到刺激后，不依赖Xist的H3K27me3和依赖Xist的H2AK119Ub修饰会以时间和空间特异性在整个Xi上积累。我们的研究结果揭示了Xist RNA、H3K27me3和H2AK119Ub标记对于雌性B细胞刺激后整个Xi上X连锁基因的表观遗传完整性的重要性。
