Enhancers, transcription factors, Mediator complex, and DNA
loops in mammalian transcription
[edit]
Regulation of
transcription in mammals. An active enhancer regulatory region of DNA is enabled to
interact with the promoter DNA region of its target gene by the 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 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.
Setting up for transcription in mammals is regulated by many cis-regulatory
elements, including core promoter and promoter-proximal elements that are
located near the transcription start sites of genes. Core promoters combined
with general transcription factors are sufficient to direct transcription initiation, but
generally have low basal activity.[7] Other important cis-regulatory modules are
localized in DNA regions that are distant from the transcription start sites. These
include enhancers, silencers, insulators and tethering elements.[8] Among this
constellation of elements, enhancers and their associated transcription
factors have a leading role in the initiation of gene transcription.[9] An enhancer
localized in a DNA region distant from the promoter of a gene can have a very
large effect on gene transcription, with some genes undergoing up to 100-fold
increased transcription due to an activated enhancer.[10]
Enhancers are regions of the genome that are major gene-regulatory elements.
Enhancers control cell-type-specific gene transcription programs, most often by
looping through long distances to come in physical proximity with the promoters of
their target genes.[11] While there are hundreds of thousands of enhancer DNA
regions,[12] for a particular type of tissue only specific enhancers are brought into
proximity with the promoters that they regulate. In a study of brain cortical neurons,
24,937 loops were found, bringing enhancers to their target promoters.[10] Multiple
enhancers, each often at tens or hundred of thousands of nucleotides distant from
their target genes, loop to their target gene promoters and can coordinate with
each other to control transcription of their common target gene.[11]
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).[13] Several cell function specific transcription factors
(there are about 1,600 transcription factors in a human cell[14]) generally bind to
specific motifs on an enhancer[15] and a small combination of these enhancer-bound
transcription factors, when brought close to a promoter by a DNA loop, govern
level of transcription 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.[16]
Enhancers, when active, are generally transcribed from both strands of DNA with
RNA polymerases acting in two different directions, producing two enhancer
RNAs (eRNAs) as illustrated in the Figure.[17] 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).[18] An activated enhancer begins
transcription of its RNA before activating transcription of messenger RNA from its
target gene.[19]