Segmental X-chromosome monosomies are compensated by transcriptional upregulation.

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.