The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread Across the X Chromosome

Mammalian genomes encode thousands of large noncoding RNAs (lncRNAs), many of which regulate gene expression, interact with chromatin regulatory complexes, and are thought to play a role in localizing these complexes to target loci across the genome. A paradigm for this class of lncRNAs is Xist, which orchestrates mammalian X-chromosome inactivation (XCI) by coating and silencing one X chromosome in females. Despite the central role of RNA-chromatin interactions in this process, the mechanisms by which Xist localizes to DNA and spreads across the X chromosome remain unknown.

Here, researchers at the Broad Institute of Harvard and MIT show that during the maintenance of XCI, Xist binds broadly across the X chromosome, lacking defined localization sites. Xist preferentially localizes to broad gene-dense regions and excludes genes that escape XCI. At the initiation of XCI in mouse embryonic stem cells, Xist initially transfers to distal regions across the X chromosome that are not defined by specific sequences. Instead, Xist RNA identifies these regions using a proximity-guided search mechanism, exploiting the three-dimensional conformation of the X chromosome to spread to distal regions in close spatial proximity to the Xist genomic locus. Initially, Xist is excluded from actively transcribed genes and accumulates on the periphery of regions containing many active genes. Xist requires its silencing domain to spread across these regions and access the entire chromosome.

The data presented in this study suggest a model for how Xist can integrate its two functions—localization to DNA and silencing of gene expression—to coat the entire X chromosome. In this model, Xist exploits three-dimensional conformation to identify and localize to initial target sites and leads to repositioning of these regions into the growing Xist compartment. These structural changes effectively pull new regions of the chromosome closer to the Xist genomic locus, allowing Xist RNA to spread to these newly accessible sites by proximity transfer. This localization strategy capitalizes on the abilities of a lncRNA to act while tethered to its transcription locus and to interact with chromatin regulatory proteins to modify chromatin structure. Beyond Xist, other lncRNAs may use a similar strategy to locate regulatory targets in three-dimensional proximity and to alter chromatin structure to establish local nuclear compartments containing co-regulated targets.

  • Engreitz JM, Pandya-Jones A, McDonel P, Shishkin A, Sirokman K, Surka C, Kadri S, Xing J, Goren A, Lander ES, Plath K, Guttman M. (2013) The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science 341(6147), 1237973. [abstract]

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