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Updated: Sep 27, 2025
08:27
A Non-random Mouse Model for Pharmacological Reactivation of Mecp2 on the Inactive X Chromosome
Published on: May 22, 2019
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Elastic dosage compensation by X-chromosome upregulation
Antonio Lentini1, Huaitao Cheng2, J C Noble1
1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Nature Communications
|April 7, 2022
Summary
X-chromosome inactivation and X-upregulation dynamically regulate gene dosage in mammals. This study reveals sex- and lineage-specific X-upregulation tuning, challenging traditional dosage compensation models.
Area of Science:
- Genetics
- Developmental Biology
- Epigenetics
Background:
- Mammalian dosage compensation relies on X-chromosome inactivation (XCI) and X-upregulation.
- The precise dynamics and regulatory links between these processes are not fully understood.
Purpose of the Study:
- To dissect the separate effects of X-upregulation and XCI on RNA levels during mouse development.
- To elucidate the regulatory link between X-upregulation and XCI.
Main Methods:
- Allele-resolved single-cell RNA sequencing.
- Chromatin accessibility profiling.
- Analysis of mouse development.
Main Results:
- X-upregulation elastically tunes gene expression dosage in a sex- and lineage-specific manner.
- Male cells upregulate X-chromosomes upon zygotic genome activation; females exhibit two upregulation waves linked to imprinted and random XCI.
- Xist ablation impairs female X-upregulation, and cells with two active X chromosomes show distinct expression patterns.
Conclusions:
- The study challenges the conventional model of dosage compensation, revealing complex, dynamic X-upregulation mechanisms.
- These findings explain how transcript copy numbers are maintained across developmental stages despite potential dose imbalances.
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