Abstract

Whilst we have the technical ability to sequence human genomes at scale, we lack the knowledge to understand what most of that sequence does. Most of the human genome (>90%) does not contain protein-coding genes and there are vast tracts of inter-genic space. Much of that genomic space contains enhancers that regulate the expression of genes in time and space. In contrast to the 20,000 or so genes in our genome, there may be hundreds of thousands, or even millions, of enhancers. Remarkably, enhancers can be found as far away as 1 megabase from the target gene whose expression they control, and they can also be embedded in the introns of other genes several genes away from their target gene. In the face of this regulatory complexity how can we understand the functional significance of genetic variation in the non-coding genome? It is hard to envisage how distant enhancers function if one only considers the genome as a linear DNA sequence. Rather, three-dimensional chromatin folding in the nucleus must play a fundamental role in enhancer-promoter communication. I will describe our work using different experimental approaches to investigate and manipulate the three-dimensional folding of the mammalian genome at genetically defined long-range regulatory elements.