Transcriptional enhancers in development and disease

Abstract

Distal transcription enhancers are cis-regulatory elements that promote gene expression, enabling spatiotemporal control of genetic programs such as those required in metazoan developmental processes. Because of their importance, their disruption can lead to disease.

Figure 1

Enhancers in development and their structural features. (a) Enhancers (colored rectangles) modularly drive gene expression at particular time points and in particular tissues (arrows) by integrating inputs (transcription factors (circles), time points when they are expressed (T1, T2, T3) and cell lineages (colors)). For example, the orange enhancers promote expression of the top two genes in liver, but at different time points (T2 and T3). The enhancer in the top gene requires binding of two transcription factors for activation in T3. (b) Schematic representation of a segment of DNA wrapped in nucleosomes displaying enhancer genomic features. Histone modifications are represented by blue, green (activating) and red (repressive) ovals attached to nucleosomes. Poised and active enhancers display different histone modifications and are associated with different trans-factors. Poised enhancers without H3K27me3 have also been identified [16] but are not shown for clarity. Pioneer TFs pre-specify enhancers that will become active later. Unmethylated CpG islands can be found in pre-specified but inactive enhancers. Enhancers can be located tens to hundreds of kilobases away from genes; active enhancers interact with promoters looping out intervening chromatin. eRNAs are products of transcription of active enhancer sequences by RNA polymerase II (Pol II).

Figure 2

Genome-wide studies identify disease-associated alleles. (a) GWASs compare the allelic frequencies of SNPs across the entire genome in case and control populations. A statistically significant difference in the allelic frequencies between cases and controls constitutes an association with disease. In this example, a guanine (G) at SNP2 is associated with the disease. (b) Only a fraction of all known SNPs that are sufficient to tag haplotypes (gray and dashed boxes) are genotyped. The actual causal allele can be another SNP (yellow circle) in the same haplotype block. In the example, the SNP might not be a non-coding variation affecting expression of the gene shown at the top left. Experimental evidence can be used to identify regulatory sequences that harbor SNPs and that are thus likely to have a role in the disease, as illustrated by the H3K27ac and H3K4me1 signals. Functional tests of the candidate sequences spanning the putative disease SNP are performed to identify allelic-specific effects on gene expression using reporter genes.