High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation

The Xist long noncoding RNA (lncRNA) is essential for X-chromosome inactivation (XCI), the process by which mammals compensate for unequal numbers of sex chromosomes^{1, 2, 3}. During XCI, Xist coats the future inactive X chromosome (Xi)⁴ and recruits Polycomb repressive complex 2 (PRC2) to the X-inactivation centre (Xic)⁵. How Xist spreads silencing on a 150-megabases scale is unclear.

Here a team led by researchers at Harvard Medical School generated high-resolution maps of Xist binding on the X chromosome across a developmental time course using CHART-seq. They found that in female cells undergoing XCI de novo, Xist follows a two-step mechanism, initially targeting gene-rich islands before spreading to intervening gene-poor domains. Xist is depleted from genes that escape XCI but may concentrate near escapee boundaries. Xist binding is linearly proportional to PRC2 density and H3 lysine 27 trimethylation (H3K27me3), indicating co-migration of Xist and PRC2. Interestingly, when Xist is acutely stripped off from the Xi in post-XCI cells, Xist recovers quickly within both gene-rich and gene-poor domains on a timescale of hours instead of days, indicating a previously primed Xi chromatin state. The researchers conclude that Xist spreading takes distinct stage-specific forms. During initial establishment, Xist follows a two-step mechanism, but during maintenance, Xist spreads rapidly to both gene-rich and gene-poor regions.

Simon MD, Pinter SF, Fang R, Sarma K, Rutenberg-Schoenberg M, Bowman SK, Kesner BA, Maier VK, Kingston RE, Lee JT. (2013) High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation. Nature [Epub ahead of print]. [abstract]