Ohno's hypothesis postulates that upregulation of X-linked genes rectifies their dosage imbalance relative to autosomal genes, which are present in two active copies per cell. Here we have dissected X-chromosome upregulation into the kinetics of transcription, inferred from allele-specific single-cell RNA sequencing data from somatic and embryonic mouse cells. We confirmed increased X-chromosome expression levels in female and male cells and found that the X chromosome achieved upregulation by elevated burst frequencies. By monitoring transcriptional kinetics in differentiating female mouse embryonic stem cells, we found that increased burst frequency was established on the active X chromosome when X inactivation took place on the other allele. Thus, our study provides mechanistic insights into X-chromosome upregulation.
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The computational code used for calculations and plotting of data is available at https://sourceforge.net/projects/kinetics-of-x-upregulation.
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This study was made possible by grants to B.R. from the Ragnar Söderberg Foundation, the Swedish Research Council (2017-01723) and Åke Wiberg’s Foundation; and grants to R.S. from the European Research Council (648842) and the Swedish Research Council (2017-01062). The authors thank D. Camsund for providing insightful comments to the manuscript.
The authors declare no competing interests.
Peer review information Anke Sparmann was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Larsson, A.J.M., Coucoravas, C., Sandberg, R. et al. X-chromosome upregulation is driven by increased burst frequency. Nat Struct Mol Biol 26, 963–969 (2019). https://doi.org/10.1038/s41594-019-0306-y
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