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Gene's Regulatory Element

A gene consists of a transcriptional region and a


regulatory region.
The transcriptional region is the part of DNA to
betranscribedinto a primary transcript (an RNA
molecule complementary to the transcriptional
region).
The regulatory region can be divided intocis-
regulatory(or cis-acting) elements andtrans-
regulatory(or trans-acting) elements.
The cis-regulatory elements are the binding
sites oftranscription factorswhich are the
proteins that, upon binding with cis-regulatory
elements, can affect (either enhance or repress)
transcription.

The cis-acting elements may be divided into the


following four types:-(1)Promoter.
(2)Enhancer.
(3)Silencer.
(4)Response element.
(1)Promoter
Promoteris the DNA region where the
transcription initiation takes place.
In prokaryotes, the sequence of a promoter is
recognized by thesigma () factorof the RNA
polymerase.
In eukaryotes, it is recognized by
E. coli
specifictranscription factors.
E. colihas five sigma factors:
Sigma 70: Regulate expression of most genes.
Sigma 32: Regulate expression of heat shock
proteins.
Sigma 28: Regulate expression of flagellar
operon (involved in cell motion).
Sigma 38: Regulate gene expression against
Eukaryotes
The most common promoter element in
eukaryotic protein genes is theTATA box, located
at -35 to -20. Its consensus sequence,TATAAA, is
quite similar to the -10 region of the Sigma 70
recognition site. Another promoter element is
called theinitiator(Inr).
It has the consensus sequence
PyPyAN(T/A)PyPy, where Py denotes pyrimidine
(C or T), N = any, and (T/A) means T or A.
The base A at the third position is located at +1
(the transcriptional start site).
TATA box and initiator are thecore promoter
elements.
There are other elements often located within
The protein which interacts with the initiator
and TATA box is known as theTATA-box binding
protein (TBP), which recognizes not only the
core promoter of protein genes, but also RNA
promoters.
It is a subunit of the general transcription factor
TFIID.
In eukaryotes, transcription requires several
different general transcription factors and, in
most cases, the regulatory transcription factors.
Example: thepromoter region of theIL-2gene,
which contains TATA box and the binding sites of
transcription factors, NFAT, Oct-1, NF-B and AP-
(2)Enhancer
The element that, upon binding with
transcription factors, can enhance transcription.
The transcription factors that bind to enhancers
are calledtranscriptional activators.
It may be located either upstream or
downstream of the transcriptional initiation site.
However, most of them are located upstream.
In prokaryotes, enhancers are quite close to the
promoter, but eukaryotic enhancers could be far
from the promoter. A few examples are given
below.
E. coli
glnAgene

The enhancer of theglnAgene is located about


120 bp from the start site, containing two binding
sites for the transcription factor
nitrogen regulatory protein C(NTRC).
YeastGAL1andGA
L10genes

BothGAL1andGAL10genes are regulated by


the same enhancer between them.
The two genes are transcribed along opposite
directions.
Therefore, the enhancer is located upstream of
both transcriptional start sites. It is also
calledupstream activating sequences(UAS),
Human globin gene
cluster

The human globin gene cluster is controlled


by an enhancer region comprising HS1 to HS4,
which contain the binding sites of GATA-1, NF-E2,
AP-1 and other transcriptional activators.
This region is known as thelocus control
region(LCR), which regulates the expression of
all five genes(, G, A, and ), even though
the distance between HS4 and the gene is as
far as 60 kb.
Examples of transcriptional
activators in mammals
Transcripti Transcriptio
Consensus Consensus
on n
Sequence Sequence
Activator Activator
PuGPuCATG
AP-1 TGAGTCA p53
PyCPy
CCC(A/C)N(C GGGPuNTP
AP-2 NF-kB
/G)3 yPyCC
Oct-1 ATGCAAAT NFAT GGAGAPu
GATA-1 (A/T)GATAPu NF-E2 TGACTCA
*Pu = Purine (A or G); Py = Pyrimidine (C or T); N
= any.
(3)Silencer
The element that, upon binding with
transcription factors, can repress transcription.
The transcription factors that bind to silencers
are calledrepressors.
In prokaryotes, silencers are known
asoperators, found in many genes such
aslacoperon andtrpoperon.
In eukaryotes, the following genes have been
demonstrated to contain silencers:-(i)Human
globin gene
(ii)Human CD95(Fas/APO-1) gene.
(iii)Human dopamine beta-hydroxylase (DBH)
gene.
In a few cases, a DNA element may act either as
an enhancer or a silencer, depending on the
binding protein.
For example, certain genes contain an element
calledE box(consensus CACGTG) which can bind
either Max/Myc dimer or Max/Mad dimer.
The Max/Myc dimer activates transcription,
whereas the Max/Mad dimer suppresses
(4)Response element
transcription of these genes.

The recognition site of certain transcription


factors.
Most of them are located within 1 kb from the
transcriptional start site.
Eukaryotic response elements
Response Transcription Consensus
Element Factor Sequence
CRE CREB TGACGTCA
Estrogen AGGTCANNNT
ERE
receptor GACCT
Glucocorticoid AGAACANNNT
GRE
receptor GTTCT
Heat shock GAANNTTCNN
HSE
factor GAA
Serum
SRE response CC(A/T)6GG
factor
*(A/T)6means six A or T; N = any.
The cAMP response element (CRE) interacts
with CREB (CRE-binding protein), which is
regulated by cAMP.
Estrogen response element (ERE) and
glucocorticoid response element (GRE) are the
recognition sites of estrogen receptor and
glucocorticoid receptor, respectively.
Heat shock response element (HSE) is present
in heat shock protein genes.
In response to external stress (e.g. high
temperature), the heat shock factor (HSF) will
interact with HSE, stimulating expression of heat
shock proteins.
Serum response element (SRE) binds to serum
response factor (SRF), which can be activated by
many growth factors in serum.
The Fos subunit ofAP-1is encoded by a gene
containing SRE.
Fos is known to play an important role in cell
cycle progression.