马萨诸塞州总医院Jeannie T. Lee小组在研究中取得进展。他们的论文发现了SIRT7调节剂量补偿并保护女性X染色体。这一研究成果发表在2026年6月10日出版的国际学术期刊《自然》上。

将SIRT7作为小鼠模型，小组研究了导致性别差异的机制，发现Sirt7^-/-雌性老鼠一生的健康状况都在下降。值得注意的是，SIRT7优先定位于性染色体。在女性个体中，SIRT7的缺失影响X染色体失活，这是剂量补偿的第一个环节，可以平衡男性和女性之间X连锁基因的表达。Xist被过度表达，基因沉默变得更有效。

然而，SIRT7缺失对活性X （X_a）染色体的影响最大。X_a染色体在组蛋白H3的Lys36位点高度乙酰化，结构紊乱，易于DNA损伤和过度表达。增加的X染色体表达导致基因组失衡和增强的X染色体上调-剂量补偿的第二臂，平衡x染色体和常染色体基因表达。这些数据揭示了SIRT7与性染色体之间的重要串扰，SIRT7保护X染色体的完整性和与常染色体的剂量平衡。该研究组提出SIRT7生物学中的性别偏见可以部分解释为对性染色体的不平等影响。

据介绍，Sirtuins是一种脱乙酰酶，与哺乳动物的应激反应和寿命有关。虽然已经注意到它们对两性疾病的不同影响，但根本原因尚不清楚。

附：英文原文

Title: SIRT7 regulates dosage compensation and safeguards the female X chromosome

Author: Simonet, Nicolas G., Thackray, Joshua K., Kesner, Barry, Guitart-Solanes, Anna, Serra, Franois, Espinosa-Alcantud, Maria, Lappala, Anna, Marn-Gual, Laia, Marn-Garca, Cristina, Weissbein, Uri, Castell-Garca, Josema, Bauer, Moritz, Wang, Danni, Rovirosa, Lloren, Tischfield, Jay, Serrano, Lourdes, Payer, Bernhard, Ruiz-Herrera, Aurora, Vazquez, Berta N., Javierre, Biola M., Vaquero, Alejandro, Lee, Jeannie T.

Issue&Volume: 2026-06-10

Abstract: 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.

DOI: 10.1038/s41586-026-10645-x

Source: https://www.nature.com/articles/s41586-026-10645-x