Aging promotes reactivation of the Barr body at distal chromosome regions [RNA organs]

Decades ago, evidence of age-related reactivation of a single gene on the female inactive X chromosome was observed in mice. While stable silencing of the Barr body is crucial for balancing gene dosage between sexes, it remained unclear whether silencing is maintained during aging. Here, we employed allele-specific multi-omics approaches to capture a comprehensive catalog of genes escaping X chromosome inactivation throughout mouse development and aging. We found substantially elevated escape rates during aging across organs, occurring in multiple distinct cell types and concentrated at distal chromosome regions. Consistently, chromatin accessibility was increased across multiple megabases at chromosome ends, affecting regulatory elements of escapees. Since several age-specific escapees are linked to human diseases, their elevated expression in females might contribute to sex-biased disease progression observed during aging.数十年前，研究人员在小鼠体内观察到雌性个体失活X染色体上的单个基因出现与衰老相关的重新激活现象。尽管巴氏小体（Barr body）的稳定沉默对维持两性间基因剂量平衡至关重要，但此前学界仍不清楚该沉默状态在衰老过程中是否能够得以维持。本研究采用等位基因特异性多组学（allele-specific multi-omics）方法，全面绘制了小鼠发育及衰老全过程中逃脱X染色体失活的基因目录。研究发现，衰老过程中各器官的X染色体失活逃逸率显著升高，该现象累及多种不同细胞类型，且集中分布于染色体远端区域。与之相一致的是，染色体末端数兆碱基（megabases）范围内的染色质可及性显著提升，进而影响逃逸基因的调控元件。鉴于部分年龄特异性逃逸基因与人类疾病存在关联，雌性个体中这些基因的表达上调可能促成了衰老过程中所观察到的性别偏向性疾病进展。