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X Chromosome Dosage Compensation During Human Early Embryonic Development


Mammalian embryonic development is one of the most complex biological processes that involves multiple epigenetic events. One of the major epigenetic processes is X chromosome dosage compensation in female mammalian cells harboring two Xchromosomes. The balance of X-linked gene levels between male and female cells can be achieved by X chromosome inactivation (XCI) or X chromosome dampening (XCD). Most of our knowledge about this complex process comes from mouse studies. Through decades of research, it has been established that the long-noncoding RNA Xist orchestrates XCI in mice. However, recent publications revealed intriguing epigenetic differences of the X chromosome and Xist function between mouse and human. In human, a different form of dosage compensation acts in preimplantation embryos and results in a dampening, but not silencing, of genes on both X chromosomes (XCD). Additionally, the localization of XIST lncRNA to the dampened X chromosome, indicates that XIST RNA can be expressed without inducing silencing, which has never been observed in the mouse. Similar to the human pre-implantation embryo, XIST is also expressed in female human primordial germ cells (hPGCs) after the inactive X chromosome is reactivated. In our work, we also demonstrate that similar to preimplantation human blastocysts X chromosome dampening is taking place in hPGCs in vivo. Additionally, using single cell RNA sequencing we demonstrate that expression of XIST in female hPGCs correlates with downregulation of X linked genes. Lastly, we demonstrate that primate specific lncRNA XACT, that has been described in the literature as pluripotency specific lncRNA, is also explicitly expressed from both active X chromosomes in hPGCs.

To address the question whether XIST is mediating X chromosome dampening we have performed functional experiments in na ve human embryonic stem cell (ESC) lines that capture the preimplantation state of the X with XIST RNA expression from the active X chromosome and X chromosome dampening (XCD). We show that XIST deletion results in upregulation of dampened X linked genes. Additionally, we demonstrate for the first time that XIST spreads to specific autosomal regions in naive pluripotent stem cells and regulate their levels. However, it still remains unclear whether XIST has a role in regulating autosomal genes during early development in vivo.

Taken together, our studies reveal insights into how epigenetic mechanisms differ between mouse and human, increase our knowledge of X chromosome regulation, and create strong bases to understand transmission of X-linked diseases through the generations.

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