Comprehensively characterizing evolutionarily conserved differential dosage compensations of the X chromosome during development and in diseases

The active X chromosome in mammals is upregulated to balance its dosage to autosomes during evolution. However, it is elusive why the currently known dosage compensation machinery showed uneven and small influence on X genes, necessitating systemic investigation of X dosage in different angles and identification of new dosage regulators. Here, based on >20,000 transcriptomes, we identified two X gene groups (genome ploidy-sensitive [PSX] and ploidy-insensitive [PIX] genes), showing distinct but evolutionarily-conserved (in both primates and mouse) dosage compensations (termed X-over-Autosome dosage Ratio, or XAR). We then explored XAR in diseases and in stem cells, where XAR is potentially important. We demonstrated that XAR-PIX was downregulated while XAR-PSX upregulated across cancer types at both RNA and protein levels. In contrast, XAR-PIX was upregulated while XAR-PSX downregulated during stem cell differentiation. Interestingly, XAR-PIX, but not XAR-PSX, was significantly lower and associated with autoantibodies and inflammation in lupus patients, suggesting that insufficient dosage of PIX genes may contribute to lupus pathogenesis. We further identified and experimentally validated two new XAR regulators, TP53 and ATRX. Collectively, we provided insights to further unravel the mystery of X dosage compensation in mammals and its pathophysiological roles in human diseases.