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This study identifies successive stages of somatic cell reprogramming to induced pluripotency and also establishes requirements for reactivation of the inactive X chromosome.
We show that the sequence by which marks on the inactive X chromosome are reversed during reprogramming resembles the inverse order of developmental X inactivation for several marks but deviates from this chronology for marks associated with resistance to reprogramming. DNA methylation is particularly persistent, and its eventual removal appears to be independent of Tet enzymes. This study establishes a valuable foundation exploitable for many applications, including staging of reprogramming cultures, isolation of intermediates, and to uncover mechanistically how cells transition toward pluripotency.