Regulation of gene expression

Regulation of gene expression (or gene regulation) includes the processes that cells and
viruses use to regulate the way that the inIormation in genes is turned into gene products.
Although a Iunctional gene product can be an RNA, the majority oI known mechanisms regulate
protein coding genes. Any step oI the gene's expression may be modulated, Irom DNA-RNA
transcription to the post-translational modiIication oI a protein.
Gene regulation is essential Ior viruses, prokaryotes and eukaryotes as it increases the versatility
and adaptability oI an organism by allowing the cell to express protein when needed.
Gene regulation drives the processes oI cellular diIIerentiation and morphogenesis, leading to the
creation oI diIIerent cell types in multicellular organisms where the diIIerent types oI cells may
possess diIIerent gene expression proIiles though they all possess the same genome sequence.
Regulated stages of gene expression
Any step oI gene expression may be modulated, Irom the DNA-RNA transcription step to post-
translational modiIication oI a protein. The Iollowing is a list oI stages where gene expression is
regulated, the most extensively utilised point is Transcription Initiation:

odification of DNA
In eukaryotes, the accessibility oI large regions oI DNA can depend on its chromatin structure,
which can be altered as a result oI histone modiIications directed by DNA methylation, DNA-
binding protein. Hence these modiIications may up or down regulate the expression oI gene.
Certain oI these modiIications that regulate gene expression are inheritable and are reIerred to as
epigenetic regulation.
emical
Methylation oI DNA is a common method oI gene silencing. DNA is typically methylated by
methyltransIerase enzymes on cytosine nucleotides in a CpG dinucleotide sequence (also called
"CpG islands" when densely clustered). Analysis oI the pattern oI methylation in a given region
oI DNA (which can be a promoter) can be achieved through a method called bisulIite mapping.
Methylated cytosine residues are unchanged by the treatment, whereas unmethylated ones are
changed to uracil. The diIIerences are analyzed by DNA sequencing or by methods developed to
quantiIy SNPs, such as Pyrosequencing (Biotage) or MassArray (Sequenom), measuring the
relative amounts oI C/T at the CG dinucleotide. Abnormal methylation patterns are thought to be
involved in oncogenesis.
Structural
Transcription oI DNA is dictated by its structure. In general, the density oI its packing is
indicative oI the Irequency oI transcription. Octameric protein complexes called nucleosomes are
responsible Ior the amount oI supercoiling oI DNA, and these complexes can be temporarily
modiIied by processes such as phosphorylation or more permanently modiIied by processes such
as methylation. Such modiIications are considered to be responsible Ior more or less permanent
changes in gene expression levels.
Histone acetylation is also an important process in transcription. Histone acetyltransIerase
enzymes (HATs) such as CREB-binding protein also dissociate the DNA Irom the histone
complex, allowing transcription to proceed. OIten, DNA methylation and histone deacetylation
work together in gene silencing. The combination oI the two seems to be a signal Ior DNA to be
packed more densely, lowering gene expression.
Regulation of transcription
Regulation oI transcription controls when transcription occurs and how much RNA is created.
Transcription oI a gene by RNA polymerase can be regulated by at least Iive mechanisms:
O Specificity factors alter the speciIicity oI RNA polymerase Ior a given promoter or set oI
promoters, making it more or less likely to bind to them (i.e., sigma Iactors used in
prokaryotic transcription).

O Repressors bind to non-coding sequences on the DNA strand that are close to or
overlapping the promoter region, impeding RNA polymerase's progress along the strand,
thus impeding the expression oI the gene.
O eneral transcription factors position RNA polymerase at the start oI a protein-coding
sequence and then release the polymerase to transcribe the mRNA.
O Activators enhance the interaction between RNA polymerase and a particular promoter,
encouraging the expression oI the gene. Activators do this by increasing the attraction oI
RNA polymerase Ior the promoter, through interactions with subunits oI the RNA
polymerase or indirectly by changing the structure oI the DNA.
O nancers are sites on the DNA helix that are bound to by activators in order to loop the
DNA bringing a speciIic promoter to the initiation complex. Enhancers are much more
common in eukaryote than prokaryotes, where only a Iew examples exist (to date).
!ost-transcriptional regulation
AIter the DNA is transcribed and mRNA is Iormed, there must be some sort oI regulation on
how much the mRNA is translated into proteins. Cells do this by modulating the capping,
splicing, addition oI a Poly(A) Tail, the sequence-speciIic nuclear export rates, and, in several
contexts, sequestration oI the RNA transcript. These processes occur in eukaryotes but not in
prokaryotes. This modulation is a result oI a protein or transcript that, in turn, is regulated and
may have an aIIinity Ior certain sequences.
Regulation of translation
The translation oI mRNA can also be controlled by a number oI mechanisms, mostly at the level
oI initiation. Recruitment oI the small ribosomal subunit can indeed be modulated by mRNA
secondary structure, antisense RNA binding, or protein binding. In both prokaryotes and
eukaryotes, a large number oI RNA binding proteins exist, which oIten are directed to their
target sequence by the secondary structure oI the transcript, which may change depending on
certain conditions, such as temperature or presence oI a ligand (aptamer). Some transcripts act as
ribozymes and selI-regulate their expression.
xamples of gene regulation
O Enzyme induction is a process in which a molecule (e.g., a drug) induces (i.e., initiates or
enhances) the expression oI an enzyme.
O The induction oI heat shock proteins in the Iruit Ily Drosophila melanogaster.
O The Lac operon is an interesting example oI how gene expression can be regulated.
O 'iruses, despite having only a Iew genes, possess mechanisms to regulate their gene
expression, typically into an early and late phase, using collinear systems regulated by
anti-terminators (lambda phage) or splicing modulators (HI').

ircuitry
Up-regulation and down-regulation
Up-regulation is a process that occurs within a cell triggered by a signal (originating internal or
external to the cell), which results in increased expression oI one or more genes and as a result
the protein(s) encoded by those genes. On the converse, down-regulation is a process resulting
in decreased gene and corresponding protein expression.
O &p-regulation occurs, Ior example, when a cell is deIicient in some kind oI receptor. In
this case, more receptor protein is synthesized and transported to the membrane oI the
cell and, thus, the sensitivity oI the cell is brought back to normal, reestablishing
homeostasis.
O Down-regulation occurs, Ior example, when a cell is overstimulated by a
neurotransmitter, hormone, or drug Ior a prolonged period oI time, and the expression oI
the receptor protein is decreased in order to protect the cell.
nducible vs. repressible systems
Gene Regulation can be summarized by the response oI the respective system:
O Inducible systems - An inducible system is oII unless there is the presence oI some
molecule (called an inducer) that allows Ior gene expression. The molecule is said to
"induce expression". The manner by which this happens is dependent on the control
mechanisms as well as diIIerences between prokaryotic and eukaryotic cells.
O Repressible systems - A repressible system is on except in the presence oI some molecule
(called a corepressor) that suppresses gene expression. The molecule is said to "repress
expression". The manner by which this happens is dependent on the control mechanisms
as well as diIIerences between prokaryotic and eukaryotic cells.
%eoretical circuits
O Repressor/Inducer: an activation oI a sensor results in the change oI expression oI a gene
O negative Ieedback: the gene product downregulates its own production directly or
indirectly, which can result in
4 keeping transcript levels constant/proportional to a Iactor
4 inhibition oI run-away reactions when coupled with a positive Ieedback loop
4 creating an oscillator by taking advantage in the time delay oI transcription and
translation, given that the mRNA and protein halI-liIe is shorter
O positive Ieedback: the gene product upregulates its own production directly or indirectly,
which can result in
4 signal ampliIication

4 bistable switches when two genes inhibit each other and both have positive
Ieedback
4 pattern generation