In biology, a promoter is a region of DNA that facilitates the transcription of a particular gene. Promoters are typically located near the genes they regulate, on the same strand and upstream (towards the 5' region of the sense strand).
In order for transcription to take place, the enzyme that synthesizes RNA, known as RNA polymerase
, must attach to the DNA near a gene. Promoters contain specific DNA sequences and response elements
which provide a binding site for RNA polymerase and for proteins called transcription factors
that recruit RNA polymerase.
- In bacteria, the promoter is recognized by RNA polymerase and an associated sigma factor, which in turn are brought to the promoter DNA by an activator protein binding to its own DNA sequence nearby.
- In eukaryotes, the process is more complicated, and at least seven different factors are necessary for the binding of an RNA polymerase II to the promoter.
Promoters represent critical elements that can work in concert with other regulatory regions (enhancers, silencers, boundary elements/insulators) to direct the level of transcription of a given gene.
Identification of relative location
As promoters are typically immediately adjacent to the gene in question, positions in the promoter are designated relative to the transcriptional start site, where transcription of RNA begins for a particular gene (i.e., positions upstream are negative numbers counting back from -1, for example -100 is a position 100 base pairs upstream).
- Core promoter - the minimal portion of the promoter required to properly initiate transcription
- Transcription Start Site (TSS)
- Approximately -34
- A binding site for RNA polymerase
- General transcription factor binding sites
- Proximal promoter - the proximal sequence upstream of the gene that tends to contain primary regulatory elements
- Approximately -250
- Specific transcription factor binding sites
- Distal promoter - the distal sequence upstream of the gene that may contain additional regulatory elements, often with a weaker influence than the proximal promoter
- Anything further upstream (but not an enhancer or other regulatory region whose influence is positional/orientation independent)
- Specific transcription factor binding sites
, the promoter consists of two short sequences at -10 and -35 positions upstream
from the transcription start site. Sigma factors not only help in enhancing RNAP binding to the promoter but helps RNAP target which genes to transcribe.
- The sequence at -10 is called the Pribnow box, or the -10 element, and usually consists of the six nucleotides TATAAT. The Pribnow box is absolutely essential to start transcription in prokaryotes
- The other sequence at -35 (the -35 element) usually consists of the six nucleotides TTGACA. Its presence allows a very high transcription rate .
- Both of the above consensus sequences, while conserved on average, are not found intact in most promoters. On average only 3 of the 6 base pairs in each consensus sequence is found in any given promoter. No promoter has been identified to date that has intact consensus sequences at both the -10 and -35; it is thought that this would lead to such tight binding by the sigma factor that the polymerase would be unable to initiate productive transcription .
- Some promoters contain a UP element (consensus sequence 5’-AAAWWTWTTTTNNNAAANNN-3'; W = A or T; N = any base) centered at -50; the presence of the -35 element appears to be unimportant for transcription from the UP element-containing promoters.
It should be noted that the above promoter sequences are only recognized by the sigma-70 protein that interacts with the prokaryotic RNA polymerase. Complexes of prokaryotic RNA polymerase with other sigma factors recognize totally different core promoter sequences.
<-- upstream downstream -->
-35 -10 Gene to be transcribed
(note that the optimal spacing between the -35 and -10 sequences is 17 nt)
Probability of occurrence of each nucleotide
for -10 sequence
T A T A A T
77% 76% 60% 61% 56% 82%
for -35 sequence
T T G A C A
69% 79% 61% 56% 54% 54%
promoters are extremely diverse and are difficult to characterize. They typically lie upstream of the gene and can have regulatory elements several kilobases away from the transcriptional start site(enhancers). In eukaryotes, the transcriptional complex can cause the DNA to bend back on itself, which allows for placement of regulatory sequences far from the actual site of transcription. Many eukaryotic promoters, but by no means all, contain a TATA box
(sequence TATAAA), which in turn binds a TATA binding protein
which assists in the formation of the RNA polymerase
transcriptional complex. The TATA box typically lies very close to the transcriptional start site (often within 50 bases).
Eukaryotic promoter regulatory sequences typically bind proteins called transcription factors which are involved in the formation of the transcriptional complex. An example is the E-box (sequence CACGTG), which binds transcription factors in the basic-helix-loop-helix (bHLH) family (e.g. BMAL1-Clock, cMyc).
Detection of promoters
A wide variety of algorithms have been developed to facilitate detection of promoters in genomic sequence, and promoter prediction is a common element of many gene prediction
A major question in evolutionary biology
is how important tinkering with promoter sequences is to evolutionary change, for example, the changes that have occurred in the human lineage after separating from chimps.
Some evolutionary biologists, for example Allan Wilson, have proposed that evolution in promoter or regulatory regions may be more important than changes in coding sequences over such time frames.
The binding of a promoter sequence (P) to a sigma factor
complex (R) is a two-step process:
- R+P ↔ RP(closed). K = 107
- RP(closed) → RP(open). K = 10−2
Diseases associated with aberrant promoter function
is a major resource for gathering information on the relationship between mutations and natural variation in gene sequence and susceptibility to hundreds of diseases
, it requires a sophisticated search strategy to extract those diseases that are associated with defects in transcriptional control where the promoter is believed to have direct involvement.
This is a list of diseases that evidence suggests have some involvement of promoter malfunction, either through direct mutation of a promoter sequence or mutation in a transcription factor or transcriptional co-activator.
Keep in mind that most diseases are heterogeneous in etiology, meaning that one "disease" is often many different diseases at the molecular level, though the symptoms exhibited and the response to treatment might be identical. How diseases respond differently to treatment as a result of differences in the underlying molecular origins is partially addressed by the discipline of pharmacogenomics.
Not listed here are the many kinds of cancers that involve aberrant changes in transcriptional regulation owing to the creation of chimeric genes through pathological chromosomal translocation.
Canonical sequences and wild-type
The usage of canonical sequence for a promoter is often problematic, and can lead to misunderstandings about promoter sequences. Canonical implies perfect, in some sense.
In the case of a transcription factor binding site, then there may be a single sequence which binds the protein most strongly under specified cellular conditions. This might be called canonical.
However, natural selection may favor less energetic binding as a way of regulating transcriptional output. In this case, we may call the most common sequence in a population, the wild-type sequence. It may not even be the most advantageous sequence to have under prevailing conditions.
Recent evidence also indicates that several genes (including the proto-oncogene c-myc) have G-quadruplex motifs as potential regulatory signals.
Diseases associated with promoter elements