The Role of CTCF-Mediated Chromatin Looping in Enhancer-Promoter Communication

In vertebrates, gene transcription is performed by generic eukaryotic molecular machinery under influence of sequence-specific DNA-binding transcription factors that control gene transcription by binding to three types of gene-regulatory chromosomal DNA regions, namely promoters, enhancers and chromatin loop anchors. Promoters are defined by the presence of a transcription start site for RNAs. They usually direct productive transcription of only one of the DNA strands flanking the promoter, unless they are bi-directional. Enhancers boost the activity of gene promoters. Enhancers work in either orientation and when inserted upstream or downstream of their target promoter. Enhancers are therefore said to work in a position and orientation-independent fashion. In vertebrate animals, chromatin loop anchors are known to be directional, depending on a correctly oriented 21 bp DNA motif bound by the CCCTC-binding protein CTCF. The quality of the CTCF DNA motif, its orientation, its genomic position and the relative orientation of its left and right neighboring CTCF sites are therefore paramount to chromosome folding. In this chapter the nucleosome and the molecular activities that are known to engage gene-regulatory regions are extensively discussed and a speculative model for enhancer-promoter communication that is consistent with recent research results is sketched.