Elastic dosage compensation by X-chromosome upregulation

• Published in: Nature communications Vol. 13; no. 1; pp. 1854 - 12
• Main Authors: Lentini, Antonio, Cheng, Huaitao, Noble, J. C., Papanicolaou, Natali, Coucoravas, Christos, Andrews, Nathanael, Deng, Qiaolin, Enge, Martin, Reinius, Björn
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.04.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 38/15; 38/23; 38/39; 38/91; 631/136/2442; 631/337/176/1433; 631/532/2117; Ablation; Alleles; Animals; Blastomeres; Chromatin; Chromosomes; Compensation; Deactivation; Dosage; Dosage compensation; Dosage Compensation, Genetic; Embryogenesis; Female; Females; Gene regulation; Humanities and Social Sciences; Inactivation; Male; Mammals; Mammals - genetics; Mice; multidisciplinary; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; Science; Science (multidisciplinary); Stem cells; Transcription; Up-Regulation; X Chromosome - genetics; X Chromosome Inactivation - genetics; X chromosomes; X-chromosome inactivation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29414-1

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. The concerted dynamics of X-chromosome upregulation and X-chromosome inactivation, which collectively balance X-chromosome expression, are not well understood. Using allelic single-cell genomics, the authors characterize the dynamics of X-chromosome upregulation and inactivation along mouse embryonic and stem cell development, calling to question keys aspects of the established model of mammalian dosage compensation.