text: Up-regulated expression of genes in mammals can be initiated when signals are transmitted to the promoters associated with the genes.  Cis-regulatory DNA sequences that are located in DNA regions distant from the promoters of genes can have very large effects on gene expression, with some genes undergoing up to 100-fold increased expression due to such a cis-regulatory sequence. These cis-regulatory sequences include enhancers, silencers, insulators and tethering elements. Among this constellation of sequences, enhancers and their associated transcription factor proteins have a leading role in the regulation of gene expression.
  Enhancers are sequences of the genome that are major gene-regulatory elements.  Enhancers control cell-type-specific gene expression programs, most often by looping through long distances to come in physical proximity with the promoters of their target genes.  In a study of brain cortical neurons, 24,937 loops were found, bringing enhancers to promoters.  Multiple enhancers, each often at tens or hundred of thousands of nucleotides distant from their target genes, loop to their target gene promoters and coordinate with each other to control expression of their common target gene.
  The schematic illustration in this section shows an enhancer looping around to come into close physical proximity with the promoter of a target gene.  The loop is stabilized by a dimer of a connector protein (e.g. dimer of CTCF or YY1), with one member of the dimer anchored to its binding motif on the enhancer and the other member anchored to its binding motif on the promoter (represented by the red zigzags in the illustration).  Several cell function specific transcription factor proteins (in 2018 Lambert et al. indicated there were about 1,600 transcription factors in a human cell) generally bind to specific motifs on an enhancer and a small combination of these enhancer-bound transcription factors, when brought close to a promoter by a DNA loop, govern the level of transcription of the target gene.  Mediator (coactivator) (a complex usually consisting of about 26 proteins in an interacting structure) communicates regulatory signals from enhancer DNA-bound transcription factors directly to the RNA polymerase II (RNAP II) enzyme bound to the promoter.
  Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two eRNAs as illustrated in the Figure.  An inactive enhancer may be bound by an inactive transcription factor.  Phosphorylation of the transcription factor may activate it and that activated transcription factor may then activate the enhancer to which it is bound (see small red star representing phosphorylation of a transcription factor bound to an enhancer in the illustration).  An activated enhancer begins transcription of its RNA before activating a promoter to initiate transcription of messenger RNA from its target gene.