XACT Noncoding RNA Competes with XIST in the Control of X Chromosome Activity during Human Early Development

Abstract

SummarySex 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) XACT and XIST on active X chromosomes in both early human pre-implantation embryos and naive human embryonic stem cells. In these contexts, the 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 XACT influences XIST accumulation in cis. Our findings therefore suggest a mechanism involving antagonistic activity of XIST and XACT in controlling X chromosome activity in early human embryos, and they highlight the contribution of rapidly evolving lncRNAs to species-specific developmental mechanisms.

Epigenetic foundations of pluripotent stem cells that recapitulate in vivo pluripotency

“…83 Consistent with ICM-like pluripotency, human ES cells in these conditions display global DNA hypomethylation and the gene expression patterns of naive markers and transposons, which are reminiscent of preimplantation human embryos [84][85][86] ( Figure 5). Of particularly note, inactive X chromosome becomes active in naive-like female cells in vitro, suggesting that reactivation of X chromosome occurs during naive conversion 84,87,88 (Figure 5). Therefore, it is expected that human naive cells serve as a powerful tool for studying human early embryogenesis and human diseases.…”

Naive Pluripotent Stem Cells as a Model for Studying Human Developmental Epigenomics: Opportunities and Limitations

“…Another defining characteristic of naive hESCs is the presence of two active X chromosomes in female cells [13,22,23]. This discovery is particularly exciting because it presents a major difference from conventional hESCs, which typically have one active and one inactive X-chromosome (reflecting their postimplantation status).…”

“…This discovery is particularly exciting because it presents a major difference from conventional hESCs, which typically have one active and one inactive X-chromosome (reflecting their postimplantation status). Moreover, naive hESCs recapitulate closely the pre-X-inactivation state of the human embryo [22] and, therefore, provide a tractable cell culture model to study the process of X-chromosome inactivation in humans.…”

“…The human embryo ensures X-chromosome dosage compensation using mechanisms distinct from the mouse, potentially through the competition of opposing long noncoding RNAs, XIST and XACT [14,22]. The presence of two active X chromosomes is stable in naive hESCs, and most cells co-express XIST and XACT.…”

“…The presence of two active X chromosomes is stable in naive hESCs, and most cells co-express XIST and XACT. Interestingly, the proportion of cells with biallelic XIST transcription varies between cell lines and over passage [22,23], and it is unclear why this expression pattern should be unstable or potentially detrimental.…”