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Our body contains hundreds of cell types and they contain almost the same set of DNA. Our skin
cells differ from liver cells because of gene regulation. This controls which genes are expressed. Each
cell has different types of genes. Due to this, they have different sets of proteins. Thus, performing
different jobs in our body (Khan Academy.org, 2017).
The same basic principles apply to eukaryotic and prokaryotic gene expression control even if the
former is more complex. This expression of genes is primarily controlled at the transcription level,
particularly in initiation (Copper, 2000).
In the absence of regulatory proteins, strong promoters are generally inactive in vivo. Thus, the
transcriptional ground state is restrictive. At first viewing, interphase chromosomes might appear to be
dispersed still, several forms of chromatin can be found along these chromosomes.
http://www.epigentek.com/catalog/chromatin-immunoprecipitation.php
Euchromatin (open chromatin) forms a relaxed structure with more spacing between the
nucleosomes and is linked to regions where active transcription is taking place. Heterochromatin (closed
chromatin), conversely, forms a tightly compacted structure and is linked to regions that are
transcriptionally inactive or silent (Epigentek, 2017).
Within the large regions of active chromatin there exist shorter stretches of 100 to 300
nucleotides that exhibit an even greater (another 10-fold) sensitivity to DNase I. These hypersensitive
sites probably result from a structural conformation that favors access of the nuclease to the DNA. These
regions are often located immediately upstream from the active gene and are the location of interrupted
nucleosomal structure caused by the binding of non-histone regulatory transcription factor proteins.In
many cases, it seems that if a gene is capable of being transcribed, it very often has a DNase-
hypersensitive site(s) in the chromatinimmediately upstream (Rodwell, 2015).
There are two types of heterochromatin: constitutive and facultative. Constitutive heterochromatin
is always condensed and thus essentially inactive. It is found in the regions near the chromosomal
centromere and at chromosomal ends (telomeres). Facultative heterochromatin is at times condensed,
but at other times it is actively transcribed and, thus, uncondensed and appears as euchromatin. Of the
two members of the X chromosome pair in mammalian females, one X chromosome is almost completely
inactive transcriptionally and is heterochromatic. However, the heterochromatic X chromosome
decondenses during gametogenesis and becomes transcriptionally active during early embryogenesis
thus, it is facultative heterochromatin (Hawkins, 1996).
There are two types of gene regulation, namely positive regulation and negative regulation.
Reulation is said to be positive when the expression of genetic information is quantitatively increased by
the presence of a specific regulatory element. Regulation is negative when the expression of genetic
information is diminished by the presence of a specific regulatory element. Elements or molecules that
mediates negative regulation are said to be negative regulators, silencers, or repressors while elements
that mediates positive regulation are called positiv regulator, enhancer, or activator (Karin, 2013).
Discussing further the regulation of gene expression in eukaryotes, we go back to the interactions
between promoters and RNA polymerase II (Pol II), the enzyme responsible for the synthesis of
eukaryotic mRNAs. Although most (but not all) Pol II promoters include the TATA box and Inr (initiator)
sequences, with their standard spacing, they vary greatly in both the number and the location of
additional sequences required for the regulation of transcription. These additional regulatory sequences
are usually called enhancers in higher eukaryotes and upstream activator sequences (UASs) in yeast.
A typical enhancer may be found hundreds or even thousands of base pairs upstream from the
transcription start site, or may even be downstream, within the gene itself. When bound by the
appropriate regulatory proteins, an enhancer increases transcription at nearby promoters regardless of its
orientation in the DNA. The UASs of yeast function in a similar way, although generally they must be
positioned upstream and within a few hundred base pairs of the transcription start site. An average Pol II
promoter may be affected by a half-dozen regulatory sequences of this type, and even more complex
promoters are quite common. Successful binding of active RNA polymerase II
holoenzyme at one of its promoters usually requires the action of proteins that are of three types which
are basal transcription factors, DNAbinding transactivators, and coactivators.
The TATA box is usually located 2530 bp upstream from the transcription start site in
mammalian genes that contain it. The consensus sequence for a TATA box is TATAAA, though
numerous variations have been characterized. The human TATA box is bound by the 34 kDa TATA-
binding protein (TBP), a subunit in at least two multisubunit complexes, TFIID and SAGA/P-CAF. The
non-TBP subunits of TFIID are proteins called TBP-associated factors (TAFs). Binding of the TBP-TAF
TFIID complex to the TATA box sequence is thought to represent a first step in the formation of the
transcription complex on the promoter.
Most transcription requires the presence of additional protein complexes. Some major regulatory
protein complexes that interact with Pol II have been defined both genetically and biochemically. These
coactivator complexes act as intermediaries between the DNA-binding transactivators and the Pol II
complex. The best-characterized coactivator is the transcription factor TFIID. In eukaryotes, TFIID is a
large complex that includes TBP and ten or more TBP associated factors (TAFs).
Some TAFs resemble histones and may play a role in displacing nucleosomes during
the activation of transcription. Many DNA-binding transactivators aid in transcription initiation by
interacting with one or more TAFs. The requirement for TAFs to initiate transcription can vary greatly from
one gene to another. Some promoters require TFIID, some do not, and some require only subsets of the
TFIID TAF subunits.
Figure: Schematic showing the transcription control regions in a hypothetical mRNA-producing eukaryotic
gene transcribed
by RNA polymerase II.
In the target tissue, the hormone passes through the plasma membrane by simple diffusion and
binds to its specific receptor protein in the nucleus. The hormone-receptor complex acts by binding to
highly specific DNA sequences called hormone response elements (HREs), thereby altering gene
expression. Hormone binding triggers changes in the conformation of the receptor proteins so that they
become capable of interacting with additional transcription factors. The bound hormone-receptor complex
can either enhance or suppress the expression of adjacent genes.
Regulation at the level of translation assumes a much more prominent role in eukaryotes than in
bacteria and is observed in a range of cellular situations. In contrast to the tight coupling of transcription
and translation in bacteria, the transcripts generated in a eukaryotic nucleus. Eukaryotes have at least
three main mechanisms of translational regulation.
Figure: Translational regulation of eukaryotic mRNA
First, initiation factors are subject to phosphorylation by a number of protein kinases. The
phosphorylated forms are often less active and cause a general depression of translation in the cell.
Second, some proteins bind directly to mRNA and act as translational repressors, many of them binding
at specific sites in the 3 untranslated region (3UTR). So positioned, these proteins interact with other
translation initiation factors bound to the mRNA or with the 40S ribosomal subunit to prevent translation
initiation. Third, binding proteins, present in eukaryotes from yeast to mammals, disrupt the interaction
between eIF4E and eIF4G. The mammalian versions are known as 4E-BPs (eIF4E binding proteins).
When cell growth is slow, these proteins limit translation by binding to the site on eIF4E that normally
interacts with eIF4G. When cell growth resumes or increases in response to growth factors or other
stimuli, the binding proteins are inactivated by protein kinasedependent phosphorylation.
There are also regulatory mechanisms that act on proteins that have already been made. In these
cases, an "edit" to the protein such as removal of amino acids, or addition of a chemical modification
can lead to a change in its activity or behavior. These processing and modification steps can be targets
for regulation.
For example, some proteins must be proteolytically cleaved (chopped up) in order to become
active. The insulin used by diabetics is one example. Other proteins may have chemical groups added to
them, including methyl, phosphate, acetyl, and ubiquitin groups. Often, these groups can be added and
removed dynamically to control activity.
Addition or removal of chemical groups may regulated protein activity or the length of time a
protein remains in the cell before it undergoes "recycling." Sometimes, chemical modifications can also
determine where a protein is found in the cellfor example, in the nucleus or cytoplasm, or attached to
the plasma membrane.
Image of a protein with a phosphate group attached, showing the chemical structure of the
phosphate group, which bears a negative charge. We saw one example of this above, when we
examined how eIF-2 is inactivated by addition of a phosphate group (blocking translation). However,
many different proteins can be selectively phosphorylated, producing various effects depending on the
protein's role in the cell.
Proteins can be tagged for degradation by the addition of a chemical marker called ubiquitin.
Ubiquitin-tagged proteins are taken to the proteasome, or recycling center of the cell, and broken down
into their component parts. Ubiquitination is an important way of controlling the persistence of a protein in
the cell.
How a protein is tagged with ubiquitin and degraded. First, ubiquitin is attached to the protein. Then, the
protein is taken to the proteasome, where it is broken down and "recycled" for parts.
Image credit: "Eukaryotic translational and post-translational gene regulation: Figure 2," by OpenStax
College, Biology CC BY 4.0
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