Naik, H. C.; Narendran, P.; GAYEN, S.

In mammals, silent state of one of the X-chromosomes in female balance the X-dosage between sexes. In parallel, X to autosome imbalance due to monoallelic expression of X-linked genes relative to biallelic autosomal genes, is primarily compensated through the X-chromosome upregulation (XCU). It has been demonstrated that X-chromosome inactivation (XCI) and XCU coincides during embryogenesis, however, XCU is not global and it occurs in a gene-specific manner. The underlying mechanistic aspects of such specificity of XCU remain unknown. Here, we provide systematic and comparative analysis across eutherians (mouse, human and pig) and metatherian (opossum) embryogenesis to determine if evolutionary origins shape the XCU. Intriguingly, we show that while evolutionary older X-linked genes (predating mammalian divergence) undergo robust XCU consistently across developmental stages, younger mammalian origin genes do not. Similarly, the eutherian X-linked genes conserved in metatherian X (X ortholog) undergo robust XCU, whereas genes orthologus to metatherian autosome (Auto ortholog) exhibit weaker pattern of XCU. Further, strata-wise comparison revealed that genes in older X chromosome strata (1 and 2) consistently undergo upregulation, whereas strata 3 & 4 genes do not. Importantly, we show that different evolutionary classes of X linked genes, which undergo robust XCU, are often enriched with active chromatin marks (H3K36me3, H3K27ac and H3K4me1) relative to the autosome, suggesting that chromatin state mediate the XCU. Moreover, we show that often active-marks enrichment correlates with differential XCU dynamics of different class of genes. Taken together, our study provides significant insight into the evolutionary dynamics of XCU and underlying mechanistic framework.