Aging promotes reactivation of the Barr body at distal chromosome regions [RNA Major cardiac cell types]

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染色体上单个基因的年龄相关性再激活现象。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，但衰老过程中该沉默状态是否得以维持仍未明确。本研究采用等位基因特异性多组学方法，构建了小鼠发育与衰老过程中逃避X染色体失活的基因的全面目录。研究发现，衰老过程中各器官的基因逃避率显著升高，该现象出现在多种不同细胞类型中，并集中分布于染色体远端区域。与之相符的是，染色体末端数兆碱基范围内的染色质可及性显著提升，影响了逃避失活基因的调控元件。鉴于部分衰老特异性逃避失活的基因与人类疾病相关，它们在雌性个体中的表达上调或可导致衰老过程中观察到的性别偏倚性疾病进展。