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Significance There is growing interest in pharmacological reactivation of the inactive X chromosome (Xi) as a method of treating X-linked disorders. Indeed, unsilencing of the normal gene copies on the Xi could potentially restore expression of the missing protein for therapeutic benefit. Because general Xi reactivation would be expected to increase expression of some other X-linked genes, the in vivo consequences of any dosage imbalance must be investigated with care. Here, we use multiple mouse models to investigate systemic effects of Xi reactivation and observe a surprising tolerance to loss of Xist RNA and partial Xi reactivation. However, we also observe thatXist and XCI are protective to females during chronic stress in the gut.

Widespread organ tolerance to Xist loss and X reactivation except under chronic stress in the gut