Genome organization and long-range regulation of gene expression by enhancers

Abstract

It is now well accepted that cell-type specific gene regulation is under the purview of enhancers. Great strides have been made recently to characterize and identify enhancers both genetically and epigenetically for multiple cell types and species, but efforts have just begun to link enhancers to their target promoters. Mapping these interactions and understanding how the 3D landscape of the genome constrains such interactions is fundamental to our understanding of mammalian gene regulation. Here, we review recent progress in mapping long-range regulatory interactions in mammalian genomes, focusing on transcriptional enhancers and chromatin organization principles.

Figure 1

Comparison of coverage versus resolution for chromatin conformation capture techniques.

Figure 2

Hi-C analysis of mouse and human ESCs. The Shh enhancer and gene, marked by grey shaded boxes, lie ~1 Mb apart but contained within a conserved topological domain to allow for correct regulation of gene expression.

Figure 3

Schematic of a layered genomic organization. Top: Active and repressed regions are sequestered into separate compartments with active domains frequently looped out into the interior of the nucleus. Middle: At a higher resolution, the genome is organized into self-associating regulatory blocks or topological domains. These domains can be associated with LaminB1 and function to contain the spread of repressive regions of histone modifications during differentiation and development. The boundaries are frequently found associated with CTCF and transcribed genes. Bottom: Within a specific regulatory block active promoters and enhancers are held in proximity to increase the likelihood of association. Cohesin and Mediator have been implicated in enhancer–promoter looping in this context.