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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE256287 | GEO | 2026/03/30

REPOSITORIES: GEO

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Project description:Sex chromosome dosage differences between males and females are a significant form of natural genetic variation in many species. Like many species with chromosomal sex determination, Drosophila females have two X chromosomes, while males have one X and one Y. The model species D. melanogaster has five roughly equally sized chromosome arms, one of which is the X chromosome. However, fusions of sex chromosomes with autosomes have occurred along the lineage leading to D. pseudoobscura and D. miranda. The resulting neo-sex chromosomes are gradually evolving the properties of sex chromosomes, and neo-X chromosomes are becoming targets for the molecular mechanisms that compensate for differences in X chromosome dose between sexes. We have previously shown that D. melanogaster possess at least two dosage compensation mechanisms: the well- characterized MSL-mediated dosage compensation active in most somatic tissues, and another system active during early embryogenesis prior to the onset of MSL-mediated dosage compensation. To better understand the developmental constraints on sex chromosome gene expression and evolution, we sequenced mRNA from individual male and female embryos of D. pseudoobscura and D. miranda, from ~0.5 to 8 hours of development. Autosomal expression levels are highly conserved between these species. But, unlike D. melanogaster, we observe a general lack of dosage compensation in D. pseudoobscura and D. miranda prior to the onset of MSL-mediated dosage compensation. The extent of female bias on the X chromosomes decreases through developmental time with the establishment of MSL-mediated dosage compensation, but may do so more slowly in D. miranda than D. pseudoobscura. Thus either there has been a lineage-specific gain or loss in early dosage compensation mechanism(s), or increasing X chromosome dose may strain dosage compensation systems and make them less effective. These results also prompt a number of questions about whether species with more sex-linked genes have more sex-specific phenotypes, and how much transcript level variance is tolerable during critical stages of development.

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

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