Eukaryotic genomes are packaged into a 3-dimensional structure in the nucleus. Current methods for studying genome-wide structure are based on proximity ligation. However, this approach can fail to detect known structures, such as interactions with nuclear bodies, because these DNA regions can be too far apart to directly ligate. Accordingly, our overall understanding of genome organization remains incomplete. Here, we develop split-pool recognition of interactions by tag extension (SPRITE), a method that enables genome-wide detection of higher-order interactions within the nucleus. Using SPRITE, we recapitulate known structures identified by proximity ligation and identify additional interactions occurring across larger distances, including two hubs of inter-chromosomal interactions that are arranged around the nucleolus and nuclear speckles. We show that a substantial fraction of the genome exhibits preferential organization relative to these nuclear bodies. Our results generate a global model whereby nuclear bodies act as inter-chromosomal hubs that shape the overall packaging of DNA in the nucleus.

Plunging into a domain of silence Female mammals have two X chromosomes. One must be silenced to “balance” gene dosage with male XY cells. The Xist long noncoding RNA coats the inactive X chromosome in female mammalian cells. Chen et al. show that the Xist RNA helps recruit the X chromosome to the internal rim of the cell nucleus, a region where gene expression is silenced. Xist is recruited to the domain through an interaction with the Lamin B receptor. This recruitment allows the Xist RNA to spread across the future inactive X chromosome, shutting down gene expression. Science , this issue p. 468

The French-Canadian variant of COX-deficient Leigh syndrome (LSFC) is unique to Québec and caused by a founder mutation in the LRPPRC gene. Using whole exome sequencing, Oláhová et al. identify mutations in this gene associated with multisystem mitochondrial disease and early-onset neurodevelopmental problems in ten patients from different ethnic backgrounds.

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