$\textit{XACT}$ Noncoding RNA Competes with $\textit{XIST}$ in the Control of X Chromosome Activity during Human Early Development

Sex chromosome dosage compensation is essential in most metazoans, but the developmental timing and underlying mechanisms vary significantly, even among placental mammals. Here we identify human-specific mechanisms regulating X chromosome activity in early embryonic development. Single-cell RNA sequencing and imaging revealed co-activation and accumulation of the long noncoding RNAs (lncRNAs) $\textit{XACT}$ and $\textit{XIST}$ on active X chromosomes in both early human pre-implantation embryos and naive human embryonic stem cells. In these contexts, the $\textit{XIST}$ RNA adopts an unusual, highly dispersed organization, which may explain why it does not trigger X chromosome inactivation at this stage. Functional studies in transgenic mouse cells show that $\textit{XACT}$ influences $\textit{XIST}$ accumulation in $\textit{cis}$. Our findings therefore suggest a mechanism involving antagonistic activity of $\textit{XIST}$ and $\textit{XACT}$ in controlling X chromosome activity in early human embryos, and they highlight the contribution of rapidly evolving lncRNAs to species-specific developmental mechanisms.The research leading to these results has received funding from the European Research Council under the EpiGeneSys FP7 257082 Network of Excellence (to C.R., E.H., and P.J.R.-G.), from the Agence Nationale pour la Recherche (ANR-11-LABX-0071, to C.R. and E.H.), from the Ligue Nationale contre le Cancer (to C.R.), and from the DIM Biotherapies (to E.H. and C.P.). T.M.L.A. is supported by a fellowship from the INCa/INSERM Plan cancer (EPIG201414). P.J.R.-G. is supported by the Wellcome Trust (WT093736) and the Biotechnology and Biological Sciences Research Council (BBSRC) (BBS/E/B/000C0402)