A recent voyage of genomic discovery has, like Columbus’s trip across the Atlantic, added detail and quantitative heft to a familiar idea. Columbus, contrary to myth, did not prove that the Earth was round. That was already well understood. Rather, he provided an estimate of the Earth’s size while adding features to the global map. Similarly, genomic researchers are well aware that the genome’s regulatory features form a three-dimensional network. But much remains to be learned about the distribution of regulatory elements and how they interact, particularly since genetic variants in regulatory sequences can affect the expression of genes near and (apparently) far.
The new study, completed by researchers from Stanford University and the European Molecular Biology Laboratory (EMBL), generated molecular profiles from 75 humans who were sequenced as part of the 1,000 Genomes Project—an international collaboration to produce an extensive catalogue of human genetic variation. The researchers used epigenetic marks to identify enhancers and promoters within the subjects' genome and, using a second technology (Hi-C) were able to map how enhancers and promoters were interacting in three-dimensional space.
Whereas promoters are located close to the gene they regulate, enhancers can be far away from their target gene in terms of genomic location and might require physical interaction with the promoter of a gene to propagate the activity signal.
As well as charting the specific interactions between promoters and enhancers using genotype information, the researchers were able to find genetic associations between physically interacting regions of the genome, thus providing evidence for functional interactions between enhancers and promoters. Essentially, the researchers produced chromatin contact maps that display one of the largest collections of local and distal histone quantitative trait loci (QTLs).
The researchers presented their findings August 20 in the journal Cell, in an article entitled, “Genetic Control of Chromatin States in Humans Involves Local and Distal Chromosomal Interactions.”
“Distal QTLs are enriched within topologically associated domains and exhibit largely concordant variation of chromatin state coordinated by proximal and distal non-coding genetic variants,” wrote the authors. “Histone QTLs are enriched for common variants associated with autoimmune diseases and enable identification of putative target genes of disease-associated variants from genome-wide association studies.”
An unexpected finding was that often it was not only genetic variants in enhancers that were associated with gene expression, but also regulatory elements in promoters of a distal genes that were physically and genetically connected to the gene of interest.
Genes are known to physically interact with multiple enhancers. In addition, the team also discovered that some promoters are genetically controlled by two or more enhancers, meaning that the enhancers either work in combination to affect gene expression or compensate each other. For example, if one individual lacks a particular enhancer there might be a backup enhancer that could compensate for the loss. Such a compensation mechanism could explain why it is so difficult to identify the causal variants of complex genetic diseases.
“We know many genetic variants are associated with different diseases, but since most of them lie in the non-coding part of the genome, we often don't know what the precise mechanisms underlying these associations are,” explained Judith Zaugg, who led the study at EMBL. “Our results, and the computational approaches we have developed mean it will now be possible to take these variants and link them back to the regulatory network within the DNA to identify the specific gene that is associated with them. This might enable us to unravel the causal mechanisms behind certain inherited diseases.”
“The approach we used enables us to map links between genes and their regulatory elements,” added Fabian Grubert, who led the work at Stanford University, in Michael Snyder's lab. “Further studies in different tissues will add even more detail to the map, and hopefully will allow us to identify all the enhancers and promoters that influence a single gene under different conditions.”