[Establishing transcriptional silencing of the X chromosome during early embryogenesis]

Early development of female mammals is accompanied by transcriptional inactivation of one of their two X chromosomes. This process, known as X-chromosome inactivation, relies on monoallelic activation of the Xist gene. Xist produces a non-coding RNA that can coat the chromosome from which it is transcribed in cis and trigger its silencing. How Xist expression is controlled and how it initiates transcriptional repression are central questions for our understanding of how this chromosome-wide monoallelic program is expressed. Several trans-acting factors have been identified as regulators of Xist expression. Interestingly, some Xist activators are encoded by the X chromosome itself, thereby efficiently promoting Xist expression in females (XX) but not in males (XY). Female cells also display transient physical pairing between their two X chromosomes at the level of their Xics (X inactivation centers) during the time window when X inactivation is initiated. It has been proposed that these pairing events may play a role in Xist activation and its monoallelic regulation. Xist RNA accumulates over the X chromosome from which it is expressed and rapidly triggers the exclusion of the transcription machinery. Genic sequences are initially located outside of this Xist RNA coated domain but as they become progressively silenced they are relocated into this silent nuclear compartment created by Xist. However genes are not all silenced with the same kinetics. Furthermore, some genes can escape X inactivation and remain located outside the Xist-coated compartment. Recent findings have revealed that young, active LINE-1 retrotransposons are expressed from the inactive X chromosome and may facilitate X inactivation, particularly in regions of the X that would otherwise be prone to escape.