The organization of the genome in the nucleus and the interactions of genes with their regulatory elements are key features of transcriptional control and their disruption can cause disease. Here we report a genome-wide method, genome architecture mapping (GAM), for measuring chromatin contacts and other features of three-dimensional chromatin topology on the basis of sequencing DNA from a large collection of thin nuclear sections. We apply GAM to mouse embryonic stem cells and identify enrichment for specific interactions between active genes and enhancers across very large genomic distances using a mathematical model termed SLICE (statistical inference of co-segregation). GAM also reveals an abundance of three-way contacts across the genome, especially between regions that are highly transcribed or contain super-enhancers, providing a level of insight into genome architecture that, owing to the technical limitations of current technologies, has previously remained unattainable. Furthermore, GAM highlights a role for gene-expression-specific contacts in organizing the genome in mammalian nuclei. A technique called genome architecture mapping (GAM) involves sequencing DNA from a large number of thin nuclear cryosections to develop a map of genome organization without the limitations of existing 3C-based methods. Our understanding of the three-dimensional organization of the genome in the nucleus has improved dramatically as a result of both developments in microscopy and molecular methods based on chromatin conformation capture (3C). Here, Ana Pombo and colleagues present a novel method of measuring chromatin contacts, called genome architecture mapping (GAM). GAM involves sequencing DNA from a large collection of thin nuclear cryosections and, unlike 3C methods, does not require ligation to capture contacts in an unbiased manner. It overcomes some of the limitations of 3C-based methods and reveals abundant three-way contacts across the genome.

Complex multi-enhancer contacts captured by genome architecture mapping