Elastic dosage compensation by X-chromosome upregulation

Antonio Lentini, Huaitao Cheng, J. C. Noble, Natali Papanicolaou, Christos Coucoravas, Nathanael Andrews, Qiaolin Deng, Martin Enge and Björn Reinius ()
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Antonio Lentini: Department of Medical Biochemistry and Biophysics, Karolinska Institutet
Huaitao Cheng: Department of Oncology and Pathology, Karolinska Institutet
J. C. Noble: Department of Medical Biochemistry and Biophysics, Karolinska Institutet
Natali Papanicolaou: Department of Medical Biochemistry and Biophysics, Karolinska Institutet
Christos Coucoravas: Department of Medical Biochemistry and Biophysics, Karolinska Institutet
Nathanael Andrews: Department of Oncology and Pathology, Karolinska Institutet
Qiaolin Deng: Department of Physiology and Pharmacology, Karolinska Institutet
Martin Enge: Department of Oncology and Pathology, Karolinska Institutet
Björn Reinius: Department of Medical Biochemistry and Biophysics, Karolinska Institutet

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract X-chromosome inactivation and X-upregulation are the fundamental modes of chromosome-wide gene regulation that collectively achieve dosage compensation in mammals, but the regulatory link between the two remains elusive and the X-upregulation dynamics are unknown. Here, we use allele-resolved single-cell RNA-seq combined with chromatin accessibility profiling and finely dissect their separate effects on RNA levels during mouse development. Surprisingly, we uncover that X-upregulation elastically tunes expression dosage in a sex- and lineage-specific manner, and moreover along varying degrees of X-inactivation progression. Male blastomeres achieve X-upregulation upon zygotic genome activation while females experience two distinct waves of upregulation, upon imprinted and random X-inactivation; and ablation of Xist impedes female X-upregulation. Female cells carrying two active X chromosomes lack upregulation, yet their collective RNA output exceeds that of a single hyperactive allele. Importantly, this conflicts the conventional dosage compensation model in which naïve female cells are initially subject to biallelic X-upregulation followed by X-inactivation of one allele to correct the X dosage. Together, our study provides key insights to the chain of events of dosage compensation, explaining how transcript copy numbers can remain remarkably stable across developmental windows wherein severe dose imbalance would otherwise be experienced by the cell.

Date: 2022
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DOI: 10.1038/s41467-022-29414-1

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