Single cell analysis reveals X chromosome upregulation is not global and primarily belongs to ancestral genes in pre-gastrulation embryos

Abstract

Evolution of sex chromosome dosage compensation in mammals remains poorly understood. Ohnos hypothesis state that evolution of dosage compensation occurred through two steps: first, to compensate the dosage imbalance created due to the degradation of Y chromosome in male, upregulation of X-chromosome happened. Subsequently, transmission of X-chromosome upregulation (XCU) in female led to the evolution of X-chromosome inactivation (XCI) to counteract extra dosage of X-linked genes in female cells. Here, we have profiled gene-wise dynamics of XCU in pre-gastrulation mouse embryos at single cell level and found that XCU is dynamically linked with XCI, however, XCU is not global or chromosome-wide like XCI. Therefore, our result raises question whether XCU driven the evolution of XCI. If so, then why XCI is chromosome wide while XCU is not. We propose that XCI might have evolved independent of XCU and therefore refining the current model is necessary. Separately, we show that higher occupancy of different activating factors at upregulated X-linked genes leads to enhanced transcriptional burst frequency and thereby leads to upregulation. On the other hand, our analysis indicates that extent of upregulation, enrichment of different activating marks differs between ancestral and newly acquired X-linked genes. Altogether, our study provides significant insight into the dynamics and mechanistic basis of evolution of sex chromosome dosage compensation. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY