Close encounters of the 3C kind: long-range chromatin interactions and transcriptional regulation

The transcriptional output of genes in higher eukaryotes is frequently modulated by cis-regulatory DNA elements like enhancers. On the linear chromatin template these elements can be located hundreds of kilobases away from their target gene and for a long time it was a mystery how these elements communicate. For example, in the beta-globin locus the main regulatory element, the Locus Control Region (LCR), is located up to 40-60 kb away from the beta-globin genes. Recently it was demonstrated that the LCR resides in close proximity to the active beta-globin genes while the intervening inactive chromatin loops out. Thus the chromatin fibre of the beta-globin locus adopts an erythroid-specific spatial organization referred to as the Active Chromatin Hub (ACH). This observation for the first time demonstrated a role for chromatin folding in transcriptional regulation. Since this first observation in the beta-globin locus, similar chromatin interactions between regulatory elements in several other gene loci have been observed. Chromatin loops also appear to be formed between promoters and 3'UTRs of genes and even trans-interactions between loci on different chromosomes have been reported. Although the occurrence of long-range chromatin contacts between regulatory elements is now firmly established it is still not clear how these long-range contacts are set up and how the transcriptional output of genes is modified by the proximity of cis-regulatory DNA elements. In this review I will discuss the relevance of interactions between cis-regulatory DNA elements in relation to transcription while using the beta-globin locus as a guideline.