Single-cell genomics is set to revolutionise our understanding of how epigenetic silencing works; by studying specific epigenetic marks or chromatin conformations in single cells, it is possible to ask whether they cause transcriptional silencing or are instead a consequence of the silent state. Here, we review what single-cell genomics has revealed about X chromosome inactivation, perhaps the best characterised mammalian epigenetic process, highlighting the novel findings and important differences between mouse and human X inactivation uncovered through these studies. We consider what fundamental questions these techniques are set to answer in coming years and propose that X chromosome inactivation is an ideal model to study gene silencing by single-cell genomics as technical limitations are minimised through the co-analysis of hundreds of genes.

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