Transcription regulation by distal enhancers: who's in the loop?

Abstract

Genome-wide chromatin profiling efforts have shown that enhancers are often located at large distances from gene promoters within the noncoding genome. Whereas enhancers can stimulate transcription initiation by communicating with promoters via chromatin looping mechanisms, we propose that enhancers may also stimulate transcription elongation by physical interactions with intronic elements. We review here recent findings derived from the study of the hematopoietic system.

Figure 1. Transcription factor occupancy and three-dimensional structure of the Myb locus. (A) ChIP-Seq profiles of CTCF (red), LDB1 (blue) and KLF1 (gray) at the Myb-Hbs1l intergenic region. A schematic of the area including all TF-binding sites and their distance relative to Myb TSS is shown. (B) Spatial organization of the Myb locus in erythroid cells. On top, a linear schematic of the locus is shown (as in A), with the looping events toward the promoter summarized by the gray arrow. Below, the actual model of the three-dimensional conformation of the locus in vivo is shown, for both erythroid progenitors (expressing Myb) and differentiated erythroid cells (silencing Myb expression).

Figure 2. Speculative model of enhancer-mediated long-range stimulation of transcription elongation. The upper half shows a model gene with an upstream enhancer occupied by transcription factors, elongations factors and the transcription machinery. In the absence of chromatin looping, expression of the gene is kept low due to inefficient transcriptional elongation. Enhancer looping toward the gene results in the stimulation of elongation by increased RNA pol II Ser 2 phosphorylation and high level gene expression. Structural factors involved in chromatin looping (i.e., CTCF and/or Cohesin, depicted by star symbols) possibly contribute to establishing local enhancer-gene communication.