While, strictly speaking, the term
refers to the DNA sequence that determines where a polymerase
initiates transcription, the term is often used to refer
to both a promoter and its associated -
control elements.

As noted earlier, transcription from many eukaryotic promoters
can be stimulated by control elements located thousands
of base pairs away from the transcription start site.
Such long-distance transcription-control elements, referred
to as , are common in eukaryotic genomes but
fairly rare in genomes.

The general consensus
now is that a spectrum of control elements regulates transcription
by RNA polymerase . At one extreme are ,
which can stimulate transcription from a promoter tens
of thousands of base pairs away. At the other extreme are
- elements, such as the upstream elements
controlling the HSV-I tk gene, which lose their influence
when moved 30–50 bp farther from the promoter.

About 70 percent
of mammalian genes are expressed from island promoters,
usually at much lower levels than genes with
box promoters.

The various transcription-control elements found in eukaryotic
DNA are binding sites for regulatory proteins
called .

In this approach, a DNA
regulatory element that has been identified by the kinds
of mutational analyses described above is used to identify
proteins—those proteins that bind specifically
to it. Two common techniques for detecting such cognate
proteins are footprinting and the .

Like activators,
most eukaryotic repressors are modular proteins that
have two functional domains: a domain and a
domain.

Many bacterial repressors are dimeric proteins in
which an α helix from each monomer inserts into the major
groove in the DNA helix and makes multiple, specific interactions
with the atoms there (Figure 9-29). This α helix
is referred to as the or because most of the amino acid side chains that contact
bases in the DNA extend from this helix.

The recognition
helix, which protrudes from the surface of a bacterial
repressor, is usually supported in the protein structure in
part by interactions with a second α helix just
N-terminal to it. This entire structural element, which is
present in many bacterial repressors, is called a -
.

Many eukaryotic transcription factors
that function during development contain a conserved
60-residue DNA-binding motif, called a , that
is similar to the helix-turn-helix motif of bacterial repressors.

The zinc finger is the most DNA-binding
motif encoded in the human genome and the genomes of
other mammals.

A second type of zinc-finger structure, designated the
zinc finger (because it has four conserved cysteines
in contact with the Zn2+), is found in some 50 human transcription factors.

Another structural motif present
in the DNA-binding domains of a large class of transcription
factors contains the hydrophobic amino acid at
every position in the sequence. These proteins bind
to DNA as , and mutagenesis of the leucines showed
that they were required for . Consequently, the
name leucine was coined to denote this structural
motif of a coiled coil of two α helixes.

The DNA-binding
domain of another class of dimeric transcription factors
contains a structural motif that is very similar to the basiczipper
motif except that a nonhelical loop of the polypeptide
chain separates two α-helical regions in each monomer
(Figure 9-30d). Termed a -- (bHLH), this
motif was predicted from the amino acid sequences of these
proteins, which contain an N-terminal α helix with basic
residues that interact with DNA, a middle loop region, and
a C-terminal region, with hydrophobic amino acids spaced
at intervals characteristic of an amphipathic α helix, that dimerizes
into a coiled coil. As with basic-zipper proteins, different
bHLH proteins can form heterodimers.

Biophysical studies indicate that acidic activation domains
have an unstructured, random-coil, intrinsically disordered
conformation. These domains stimulate transcription
when they are bound to a protein

Analysis of the roughly 50-bp enhancer
that regulates expression of β-interferon, an important protein
in defense against viral infections in vertebrates, provides
a good example of the structure of the DNA-binding
domains of several transcription factors bound to the several
transcription-factor-binding sites that constitute an enhancer
(Figure 9-34). The term has been coined to
describe such large DNA-protein complexes that assemble
from transcription factors as they bind to the multiple binding
sites in an enhancer.

direct binding of RNA polymerase II to DNA,
determine the site of initiation, and influence
the of transcription initiation.

- elements occur within about 200 bp
of a start site. Several such elements, containing 6–10 bp,
may help regulate a particular gene.

, which contain multiple short control elements,
may be located from 200 bp to tens of kilobases upstream
or downstream from a promoter, within an intron, or downstream
from the final exon of a gene.

, which activate or repress transcription,
bind to promoter-proximal regulatory elements and
enhancers in eukaryotic DNA.

Activation and repression domains in transcription factors
exhibit a variety of amino acid sequences and threedimensional
structures. In general, these functional domains
interact with or , which are critical
to the ability of transcription factors to modulate gene
expression.

Binding of multiple transcription factors to multiple sites
in an enhancer forms a DNA-protein complex called an