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Elastic dosage compensation by X-chromosome upregulation
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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987076/ https://www.ncbi.nlm.nih.gov/pubmed/35388014 http://dx.doi.org/10.1038/s41467-022-29414-1 |
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author | Lentini, Antonio Cheng, Huaitao Noble, J. C. Papanicolaou, Natali Coucoravas, Christos Andrews, Nathanael Deng, Qiaolin Enge, Martin Reinius, Björn |
author_facet | Lentini, Antonio Cheng, Huaitao Noble, J. C. Papanicolaou, Natali Coucoravas, Christos Andrews, Nathanael Deng, Qiaolin Enge, Martin Reinius, Björn |
author_sort | Lentini, Antonio |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8987076 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-89870762022-04-22 Elastic dosage compensation by X-chromosome upregulation Lentini, Antonio Cheng, Huaitao Noble, J. C. Papanicolaou, Natali Coucoravas, Christos Andrews, Nathanael Deng, Qiaolin Enge, Martin Reinius, Björn Nat Commun Article 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. Nature Publishing Group UK 2022-04-06 /pmc/articles/PMC8987076/ /pubmed/35388014 http://dx.doi.org/10.1038/s41467-022-29414-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lentini, Antonio Cheng, Huaitao Noble, J. C. Papanicolaou, Natali Coucoravas, Christos Andrews, Nathanael Deng, Qiaolin Enge, Martin Reinius, Björn Elastic dosage compensation by X-chromosome upregulation |
title | Elastic dosage compensation by X-chromosome upregulation |
title_full | Elastic dosage compensation by X-chromosome upregulation |
title_fullStr | Elastic dosage compensation by X-chromosome upregulation |
title_full_unstemmed | Elastic dosage compensation by X-chromosome upregulation |
title_short | Elastic dosage compensation by X-chromosome upregulation |
title_sort | elastic dosage compensation by x-chromosome upregulation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987076/ https://www.ncbi.nlm.nih.gov/pubmed/35388014 http://dx.doi.org/10.1038/s41467-022-29414-1 |
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