Reversal of X chromosome inactivation: lessons from pluripotent reprogramming of mouse and human somatic cells

For reprints contact: [email protected] X chromosome inactivation (XCI) is a strategy used by mammals to silence genes along one of the two female X chromosomes and equilibrate expression dosage between XY males and XX females. This epigenetically-inherited silencing is established during early embryonic development and maintained thereafter through cell divisions. Seeding of multiple repressive epigenetic marks along the inactive X chromosome (Xi) makes inactivation extremely robust and difficult to reverse upon single genetic perturbations. Reversal of XCI has, however, been observed when somatic cells are reprogrammed towards pluripotency, and in vitro reprogramming techniques have been used in recent years to dissect Xi gene reactivation mechanisms. These studies pave the way for developing novel therapeutic approaches for X-linked diseases. Here, the author reviews Xi reactivation during pluripotent reprogramming of mouse and human somatic cells, highlight recent advances and species-specific differences, and discuss the relevance for human diseases.