Sirtuin 7 regulates dosage compensation and safeguards the female X-chromosome

Sirtuins are deacetylases implicated in stress responses and longevity in mammals. Although their differential impact on disease for the two sexes have been noted, underlying reasons are not known. Here, using Sirtuin 7 (SIRT7) as a model in mice, we probe mechanisms leading to sex differences and find that Sirt7-/- females have decreased fitness throughout the lifespan. Intriguingly, SIRT7 preferentially localizes to the sex chromosomes. In females, SIRT7 loss affects “X-chromosome inactivation” (XCI), the 1st arm of dosage compensation that equalizes X-linked gene expression between males and females. Xist is overexpressed and gene silencing becomes more efficient. Surprisingly, however, SIRT7 loss has greatest impact on the active X (Xa). The Xa becomes hyperacetylated on H3K36ac, structurally disorganized, prone to DNA damage, and overexpressed. Increased Xa expression leads to genome imbalance and augmented “X-chromosome upregulation” (XCU) — the 2nd 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 Sirtuin 7 biology can be explained in part by unequal effects on the sex chromosomes. This SuperSeries is composed of the SubSeries listed below.