X-chromosome upregulation operates on a gene-by-gene basis at RNA and protein levels

Gene dosage compensation mechanisms are crucial for mammalian development. In mice, recent findings show that cells can sense the number of X chromosomes. Loss or inactivation of one of the two X chromosomes is compensated by upregulating the remaining active X chromosome, a process termed X-chromosome upregulation (XCU). However, how cells sense X-chromosome dosage and induce XCU remains unclear. Here, we show that heterozygous X chromosome fragment deletions in mouse pluripotent stem cells induces XCUin trans, and that compensation takes place at the mRNA and protein level. Furthermore, we found that inducing gene silencingin cison autosomes induces gene dosage compensationin trans. This work provides significant insights into the molecular foundations of mammalian gene dosage compensation.