Genome Architecture Mapping
Reference Number TO 03-00390
The organization of the genome in the nucleus as well as the interactions of genes with their regulatory elements are key features of transcriptional control. Their disruption may cause severe diseases. Technologies based on chromosome conformation capture (3C) have profoundly expanded our understanding of the role of genome architecture in gene regulation. However, 3C-based techniques have important limitations, many due to their reliance on digestion and ligation of the contacting DNA segments.
Genome Architecture Mapping (GAM) is a novel genome-wide method for measuring three-dimensional chromatin topology without ligation. GAM extracts spatial information by sequencing DNA from a large collection of thin nuclear sections and quantifying the frequency of locus co-segregation. GAM has the power to explore many aspects of 3D genome conformation, especially multi-way contacts between regulatory regions and target genes, and is ideally suited to the analysis of specific cell types within tissue samples. GAM reproduces general features of chromatin organization also uncovered by 3C-based methods. Strikingly, exploration of the most prominent chromatin contacts using GAM in combination with a statistical model (SLICE) identifies specific long-range contacts between active genes and enhancers across very large genomic distances. GAM also reveals an abundance of three-way contacts genome-wide, especially between the enhancers most highly occupied by pluripotency transcription factors and highly transcribed genomic regions (or super-enhancers). Our results highlight a previously inaccessible complexity in genome architecture and a major role for contacts driven by gene expression in organizing genome architecture of mammalian nuclei.
GAM will contribute to unravelling complexity in long-range gene regulation and thereby lead to identification of new targets for therapy. At the moment, we are looking for industrial partners to cooperate on optimizing and automating GAM technology.
First version of GAM established; proof of concept demonstrated.
R.A. Beagrie, Antonio Scialdone et al. (Nature 2017): Complex multi-enhancer contacts captured by Genome Architecture Mapping.