Lineage-specific dynamics of erasure of X-upregulation during inactive-X reactivation

In mammals, sex chromosome dosage is compensated through X-chromosome inactivation and active-X upregulation. It is believed that during early development, X-chromosome inactivation and active X upregulation happen in a highly coordinated fashion. However, such coordination between two X-chromosomes in other developmental contexts remains unexplored. Here, we have profiled the coordination between two X-chromosomes in female cells in different developmental contexts and cell types: pre-implantation embryos, embryonic epiblast cells, iPSC reprogramming, germ cell reprogramming, B-cell, and extra-embryonic endoderm stem (XEN) cells. Interestingly, we found that two X-chromosomes in female cells are not always coordinated; instead, it happens in a lineage-specific manner. Specially, while embryonic mouse epiblast cells, iPSC undergo erasure of X-upregulation upon reactivation of the inactive X, germ cells do not. Importantly, we show that the erasure of X-upregulation in epiblast or iPSC is potentially mediated via undifferentiated embryonic transcription Factor 1 (UTF1), which is absent or lowly expressed in late germ cells and therefore, germ cells are unable to erase upregulation. Moreover, we found that partial reactivation of the inactive X is insufficient to drive the erasure of upregulation globally, nor from their counterparts on the active X in XEN and B-cells. Finally, through a phenomenological mathematical model, we show that cross-inhibition between two X-chromosomes can reproduce the dynamics of reactivation and erasure of upregulation. Altogether, our study provides insight into the coordination between two X-chromosomes in female cells in different developmental contexts and related mechanistic aspects. Abstract Figure