Enhancers, transcription factors, mediator complex and DNA loops in
mammalian transcription  

 **Regulation of
transcription in mammals** . An active  enhancer
 "Enhancer \(genetics\)") regulatory region is
enabled to interact with the  promoter 
"Promoter \(genetics\)") region of its target  gene  by
formation of a chromosome loop. This can initiate  messenger RNA
 (mRNA) synthesis by  RNA polymerase II
 (RNAP II) bound to the promoter
at the  transcription start site 
"Transcription \(biology\)") of the gene. The loop is stabilized by one
architectural protein anchored to the enhancer and one anchored to the
promoter and these proteins are joined to form a dimer (red zigzags). Specific
regulatory  transcription factors  bind to DNA sequence motifs on the enhancer. General transcription
factors bind to the promoter. When a transcription factor is activated by a
signal (here indicated as  phosphorylation  shown by a small red star on a transcription factor on the
enhancer) the enhancer is activated and can now activate its target promoter.
The active enhancer is transcribed on each strand of DNA in opposite
directions by bound RNAP IIs. Mediator (a complex consisting of about 26
proteins in an interacting structure) communicates regulatory signals from the
enhancer DNA-bound transcription factors to the promoter.

Gene expression in mammals is regulated by many  cis-regulatory elements
 , including  core
promoters and promoter-proximal elements 
"Promoter \(genetics\)") that are located near the  transcription start sites
 of genes, 
upstream  "Upstream and downstream
\(DNA\)") on the DNA (towards the 5' region of the  sense strand
 ). Other important cis-regulatory modules
are localized in DNA regions that are distant from the transcription start
sites. These include  enhancers  "Enhancer
\(genetics\)") ,  silencers  "Silencer
\(genetics\)") ,  insulators  "Insulator
\(genetics\)") and tethering elements.  [33]  Enhancers and their associated 
transcription factors 
have a leading role in the regulation of gene expression.  [34]

 Enhancers  "Enhancer \(genetics\)") are genome
regions that regulate genes. 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.  [35]  Multiple
enhancers, each often 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 gene expression.  [35]

The illustration shows an enhancer looping around to come into 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
 ). One member of the dimer is anchored to its binding motif
on the enhancer and the other member is anchored to its binding motif on the
promoter (represented by the red zigzags in the illustration).  [36]  Several
cell function-specific transcription factors (among the about 1,600
transcription factors in a human cell)  [37]  generally bind to specific
motifs on an enhancer.  [38]  A small combination of these enhancer-bound
transcription factors, when brought close to a promoter by a DNA loop, govern
transcription level of the target gene. Mediator (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 (pol II) enzyme bound to the promoter.  [39]

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.  [40]  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 transcription factor bound to enhancer in the illustration).  [41]  An
activated enhancer begins transcription of its RNA before activating
transcription of messenger RNA from its target gene.  [42]