Recently, a unique form of X chromosome dosage compensation has been demonstrated in human preimplantation embryos, which happens through the dampening of X-linked gene expression from both X chromosomes. Subsequently, X chromosome dampening has also been demonstrated in female human pluripotent stem cells (hPSCs) during the transition from primed to naive state. However, the existence of dampened X chromosomes in both embryos and hPSCs remains controversial. Specifically, in preimplantation embryos it has been shown that there is inactivation of X chromosome instead of dampening. Here, we performed allelic analysis of X-linked genes at the single-cell level in hPSCs and found that there is partial reactivation of the inactive X chromosome instead of chromosome-wide dampening upon conversion from primed to naive state. In addition, our analysis suggests that the reduced X-linked gene expression in naive hPSCs might be the consequence of erasure of active X chromosome upregulation.

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Recently, allele-specific single-cell RNA-seq analysis has demonstrated widespread dynamic random monoallelic expression of autosomal genes (aRME) in different cell types. However, the prevalence of dynamic aRME during pregastrulation remains unknown. Here, we show that dynamic aRME is widespread in different lineages of pregastrulation embryos. Additionally, the origin of dynamic aRME remains elusive. It is believed that independent transcriptional bursting from each allele leads to dynamic aRME. Here, we show that allelic burst is not perfectly independent; instead it happens in a semicoordinated fashion. Importantly, we show that semicoordinated allelic bursting of genes, particularly with low burst frequency, leads to frequent asynchronous allelic bursting, thereby contributing to dynamic aRME. Furthermore, we found that coordination of allelic bursting is lineage specific and genes regulating the development have a higher degree of coordination. Altogether, our study provides significant insights into the prevalence and origin of dynamic aRME and their developmental relevance during early development.

SummaryRecent studies have provided substantial evidence supporting Ohno’s hypothesis that upregulation of active X chromosome genes balances the dosage relative to autosomal genes. Here, we found the evidence for erasure of active X-chromosome upregulation upon reactivation of inactive X in female cells during iPSC reprogramming and in the inner cell mass of mouse blastocyst. Moreover, our analysis revealed that the kinetics of erasure of X upregulation is tightly linked with the dynamics of X reactivation.Abstract Figure

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