Hoelzl Sarah, Hasenbein Tim P, Engelhardt Stefan, Andergassen Daniel
Institute of Pharmacology and Toxicology, Technical University Munich, Munich, Germany.
DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
Nat Aging. 2025 May 1. doi: 10.1038/s43587-025-00856-8.
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 remains unclear whether silencing is maintained during aging. Here we used 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. As several age-specific escapees are linked to human diseases, their elevated expression in females might contribute to sex-biased disease progression observed during aging.
几十年前，在小鼠中观察到雌性失活X染色体上单个基因与年龄相关的重新激活的证据。虽然巴氏小体的稳定沉默对于平衡两性之间的基因剂量至关重要，但目前尚不清楚在衰老过程中沉默是否得以维持。在这里，我们使用等位基因特异性多组学方法来获取小鼠整个发育和衰老过程中逃脱X染色体失活的基因的全面目录。我们发现，在衰老过程中，多个器官的逃脱率大幅升高，发生在多种不同的细胞类型中，并集中在染色体远端区域。一致的是，染色体末端多个百万碱基的染色质可及性增加，影响了逃脱基因的调控元件。由于一些与年龄相关的逃脱基因与人类疾病有关，它们在雌性中的表达升高可能导致衰老过程中观察到的性别偏向性疾病进展。
