X Chromosome Reactivation Dynamics Reveal Stages of Reprogramming to Pluripotency

摘要: Reprogramming to iPSCs resets the epigenome of somatic cells, including reversal X chromosome inactivation. We sought gain insight into steps underlying reprogramming process by examining means which leads reactivation (XCR). Analyzing single cells in situ, we found that hallmarks inactive (Xi) change sequentially, providing a direct readout progression. Several epigenetic changes on Xi occur in inverse order developmental inactivation, whereas others are uncoupled from this sequence. Among latter, DNA methylation has an extraordinary long persistence during reprogramming, and, like Xist expression, is erased only after pluripotency genes activated. Mechanistically, XCR requires both demethylation and silencing, ensuring undergoing faithful initiate XCR. Our study defines state multiple sequential intermediates establishes paradigm for studying cell fate transitions reprogramming.