SIRT7 regulates dosage compensation and safeguards the female X chromosome

Sirtuins are deacetylases implicated in stress responses and longevity in mammals^1,2. Although their differential impact on disease for the two sexes has been noted^3-7, 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 females^8-10. Xist is overexpressed and gene silencing becomes more efficient. However, SIRT7 loss has greatest impact on the active X (X_a) chromosome. The X_a chromosome becomes hyperacetylated at Lys36 of histone H3, structurally disorganized, prone to DNA damage and overexpressed. Increased X_a-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.