SIRT7 regulates dosage compensation and safeguards the female X chromosome

• 成果类型: Article
• 署名作者: Simonet, Nicolas G.; Thackray, Joshua K.; Kesner, Barry; Guitart-Solanes, Anna; Serra, Francois; Espinosa-Alcantud, Maria; Lappala, Anna; Marin-Gual, Laia; Marin-Garcia, Cristina; Weissbein, Uri; Castello-Garcia, Josema; Bauer, Moritz; Wang, Danni; Rovirosa, Llorenc; Tischfield, Jay; Serrano, Lourdes; Payer, Bernhard; Ruiz-Herrera, Aurora; Vazquez, Berta N.; Javierre, Biola M.; Vaquero, Alejandro; Lee, Jeannie T.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Institut de Recerca Contra la Leucemia Josep Carreras (IJC); Harvard University; Harvard Medical School; Rutgers University System; Rutgers University New Brunswick; Autonomous University of Barcelona; Autonomous University of Barcelona; Pompeu Fabra University; Barcelona Institute of Science & Technology; Centre de Regulacio Genomica (CRG); City University of New York (CUNY) System; Universite de Montreal; Universite de Montreal; Centre Hospitalier Universitaire Sainte-Justine
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-026-10645-x
• 发表日期: 2026-07-23
• 关键词: double-strand breaks; rna-polymerase-ii; INACTIVE-X; transcription initiation; genome integrity; up-regulation; chromatin; acetylation; SIRTUINS; gene

摘要

Sirtuins are deacetylases implicated in stress responses and longevity in mammals1,2. Although their differential impact on disease for the two sexes has been noted3, 4, 5, 6-7, the underlying reasons are unclear. Here, using Sirt7 as a model in mice, we examine the mechanisms leading to sex differences and find that Sirt7-/- female mice have decreased fitness throughout their lifespan. Notably, SIRT7 preferentially localizes to the sex chromosomes. In female individuals, SIRT7 loss affects X-chromosome inactivation, the first arm of dosage compensation that equalizes X-linked gene expression between males and females8, 9-10. Xist is overexpressed and gene silencing becomes more efficient. However, SIRT7 loss has greatest impact on the active X (Xa) chromosome. The Xa chromosome becomes hyperacetylated at Lys36 of histone H3, structurally disorganized, prone to DNA damage and overexpressed. Increased Xa-chromosome expression leads to genome imbalance and augmented X-chromosome upregulation-the second arm of dosage compensation that balances X-chromosome versus autosomal gene expression. These data reveal an essential crosstalk between sirtuins and the sex chromosomes, with SIRT7 safeguarding X-chromosome integrity and dosage balance with autosomes. We propose that the sex bias in SIRT7 biology can be explained in part by unequal effects on the sex chromosomes.