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Segmental X-chromosome monosomies are compensated by transcriptional upregulation.

ABSTRACT: XX mice undergo both X-chromosome inactivation (XCI) and X-chromosome upregulation (XCU) to balance X-linked gene dosage with autosomes and XY mice. XCU has also been reported in XY cells, as well as cells with a single copy of the X-chromosome (XO). The two dosage compensation processes have been shown to occur simultaneously; as one X-chromosome is inactivated, the remaining active X-chromosome becomes upregulated. However, it remains unknown if cells sense and adapt gene dosage at the chromosomal level, or on a gene-by-gene basis. Here, we demonstrate that mouse embryonic stem cells can compensate gene dosage by XCU when specific regions or genes are deleted. Compensation occurs at both the transcriptional and protein levels, and on a gene-by-gene basis. Moreover, we provide evidence for autosomal gene dosage compensation in trans. Overall, our results demonstrate that mammalian cells can sense when specific chromosome regions or genes are heterozygously deleted or inactivated, and can compensate at the transcriptional or protein level with gene specificity. Our results have important implications for our understanding of the evolution of gene dosage compensation, health, and disease.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Early Embryonic Cell, Fibroblast

SUBMITTER: Jeroen Demmers

LAB HEAD: Jeroen Demmers

PROVIDER: PXD057399 | Pride | 2025-06-19

REPOSITORIES: Pride

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Project description:Aneuploidy, an imbalance in chromosome copy numbers, causes genetic disorders, and drives cancer progression, drug tolerance, and antimicrobial resistance. While aneuploidy can confer stress resistance, it is not well understood how cells overcome the fitness burden caused by aberrant chromosomal copy numbers. Studies using both systematically generated and natural aneuploid yeasts triggered an intense debate about the role of dosage compensation, concluding that aneuploidy is transmitted to the transcriptome and proteome without significant buffering at the chromosome-wide level, and is, at least in lab strains, associated with significant fitness costs. Conversely, systematic sequencing and phenotyping of large collections of natural isolates revealed that aneuploidy is frequent and has few, if any, fitness costs in nature. To address these discrepant findings, we developed a platform that yields highly precise proteomic measurements across large numbers of genetically diverse samples and applied it to natural isolates collected as part of the 1011 genomes project (Peter, J. et al, 2018). For 613 of the isolates, we were able to match the proteomes to their corresponding transcriptomes and genomes, subsequently quantifying the effect of aneuploidy on gene expression by comparing 95 aneuploid with 518 euploid strains. We find, as in previous studies, that aneuploid gene dosage is not buffered chromosome-wide at the transcriptome level. Importantly, in the proteome, we detect an attenuation of aneuploidy by about 25% below the aneuploid gene dosage in natural yeast isolates. Furthermore, this chromosome-wide dosage compensation is associated with the ubiquitin-proteasome system (UPS), which is expressed at higher levels and has increased activity across natural aneuploid strains. Thus, through systematic exploration of the species-wide diversity of the yeast proteome, we shed light on a long-standing debate about the biology of aneuploids, revealing that aneuploidy tolerance is mediated through chromosome-wide dosage compensation at the proteome level.

			Action	DRS
	2572_rerun_Report_Protein_Pivot.tsv	Tabular
	DeletionE1.raw	Raw
	DeletionE2.raw	Raw
	DeletionE3.raw	Raw
	DeletionK1.raw	Raw

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Segmental X-chromosome monosomies are compensated by transcriptional upregulation.

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