Figuring out how one X-chromosome is silenced

Researchers now know how one of two X-chromosomes is silenced (turned off) during the development of female human embryos. Also, as well, in lab-grown human stem cells. Turning off one X-chromosome is essential in embryo development to avoid duplicated messages.

Female cells have two X-chromosomes. One X-chromosome is shut down in the earliest stages of embryo development to prevent duplicated expression (turning on) of genes from both X chromosomes.

Previous research on mouse embryos shows that a long RNA molecule called XIST actually coats regions of the turned off (silenced) DNA on the extra X chromosome, suppressing its function. However, even though XIST is turned on and functioning in human embryos, the human second X chromosome isn't silenced — until a few days later.

The difference in mouse and human embryos suggests that XIST doesn't fulfill the same role in humans as it does in mice. And, it was unclear why.

Researchers at the Paris Diderot University, Institute Curie and the Babraham Institute report in Cell Stem Cell that a second long RNA molecule, XACT — only found in humans — accumulates along with XIST on active X-chromosomes in embryos.

Unspecialised 'naïve' human embryonic stem cells show the same pattern of XACT and XIST accumulation on active X-chromosomes. This epigenetic feature of embryo development is also preserved in human stem cells cultured in the laboratory.

The two RNAs — XACT and XIST — do not overlap. Each occupies large and distinct territories on the X.

By monitoring XACT activity in stem cells, researchers believe there could be an antagonistic mechanism between XIST and XACT that controls the X-chromosome. That interplay might explain why XIST cannot shut down the X-chromosome until XACT is reduced in amount at later stages in embryo development.

"This important paper might provide the long sought-after explanation for why XIST appears unable to trigger X-chromosome inactivation during the earliest stages of human development.

"It exemplifies that mechanisms of epigenetic regulation can vary substantially between species, and that long RNA molecules can contribute to these variations."

Peter Rugg-Gunn PhD, Epigenetics Programme, The Babraham Institute, Cambridge, UK; Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute, and Center for Trophoblast Research, University of Cambridge, Cambridge, UK, and research group leader.

Abstract Highlights
XACT and XIST simultaneously coat active X chromosomes in human embryos •Naive hESCs capture the pre-inactive state with XIST and XACT co-accumulation •XIST adopts a dispersed configuration in pre-inactive cells in vitro and in vivo •XACT prevents XIST accumulation in cis in a mouse heterologous system Summary 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) 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.

This research was funded through grants provided to Dr Peter Rugg-Gunn by the Wellcome Trust and the Medical Research Council (MRC). The Babraham Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC).
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Dec 26, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

There could be antagonism between 2 molecules — XIST and XACT in humans — that controls
when the second X-chromosome in female humans is turned off. Mice — used as control animals
in place of humans — do not have the same mechanism. The XIST and XACT antagonism might
explain why XIST cannot shut off the second female X-chromosome until the amount of XACT
is reduced during later stages of the first three months of human embryo development.
Image Credit: Mouse, Public Domain; baby licensened: MouseWorks Inc.