Gene Expression

by Assist. Prof. Görke Gürel Peközer

Yıldız Technical University

Biomedical Engineering Department
Spring 2020
 Last week on BME 1532
 Central Dogma
 Transcription
 Promoters, Terminators,
 Prokaryotic Transcription
 Sigma factor
 Eukaryotic Transcription
 Regulatory DNA sequences, general transcription factors, RNA polymerase types
 mRNA proceesing
 Capping
 Polyadenylation
 Splicing
 Alternative Splicing
 Translation
 Genetic code, codon, reading frame
 tRNAs
 Ribosomes
 Over the course of embryonic development, a fertilized egg cell
gives rise to many cell types that differ dramatically in both
structure and function.
 This occurs through cell differentiation which is achieved by
changes in gene expression.
 The evidence that cells have the ability to change which genes
they express without altering the nucleotide sequence of their
DNA comes from experiments in which the genome from a
differentiated cell is made to direct the development of a
complete organism.
 If the chromosomes of the differentiated cell were altered
irreversibly during development, they would not be able to
accomplish this.
 DNA in specialized cell types of multicellular organisms still
contains the entire set of instructions needed to form a whole
organism. The various cell types of an organism therefore differ
not because they contain different genes, but because they
express them differently.
 Nearly all the cells of a multicellular organism contain the same
genome.
 However, the differences between an information-processing
nerve cell and a blood-filtering kidney cell, for example, are so
extreme that it is difficult to imagine that the two cells contain
the same DNA.
 In mammals, hundreds of different cell types carry out a range of
specialized functions that depend upon genes that are switched
on in that cell type but not in most others: for example, the β
cells of the pancreas make the protein hormone insulin, while
the α cells of the pancreas make the hormone glucagon; the B
lymphocytes of the immune system make antibodies, while
developing red blood cells make the oxygen-transport protein
hemoglobin.
 The differences between a neuron, a white blood cell, a
pancreatic β cell, and a red blood cell depend upon the precise
control of gene expression.
 A typical differentiated cell expresses only about half the genes
in its total repertoire.
 It is the expression of a different collection of genes in each cell
type that causes the large variations seen in the size, shape,
behavior, and function of differentiated cells.
 The extent of the differences in gene expression between
different cell types can be also investigated by comparing the
protein composition of cells in liver, heart, brain, and so on.
 These investigations reveal that many proteins are common to all
the cells of a multicellular organism. These housekeeping
proteins expressed from housekeeping genes include, for
example, the structural proteins of chromosomes, RNA
polymerases, DNA repair enzymes, ribosomal proteins, enzymes
involved in glycolysis and other basic metabolic processes, and
many of the proteins that form the cytoskeleton.
 In addition, each different cell type also produces specialized
proteins that are responsible for the cell’s distinctive properties.
 Besides, requirements for some gene products change over time.
 For example, the need for enzymes in certain metabolic
pathways may increase or decrease as food sources change or are
depleted.
 Or the specialized cells in a multicellular organism can alter their
patterns of gene expression in response to extracellular cues.
 For example, if a liver cell is exposed to the steroid hormone
cortisol, the production of several proteins is dramatically
increased. When the hormone is no longer present, the
production of these proteins returns to its resting level.
 Other cell types respond to cortisol differently, while some other
cell types do not respond to cortisol at all.
 The fact that different cell types often respond in different ways
to the same extracellular signal contributes to the specialization
that gives each cell type its distinctive character.
 Control of Gene Expression
 The control of gene expression is achieved at different levels since there
are many steps in the pathway leading from DNA to protein, and all of
them can in principle be regulated.
 Thus a cell can control the proteins it contains by;
1. controlling when and how often a given gene is transcribed,
2. controlling how an RNA transcript is spliced or otherwise processed,
3. selecting which mRNAs are exported from the nucleus to the cytosol,
4. regulating how quickly certain mRNA molecules are degraded,
5. selecting which mRNAs are translated into protein by ribosomes, or
6. regulating how rapidly specific proteins are destroyed after they have
been made;
7. regulating the activity of individual proteins
Transcriptional Control of Gene Expression
 For most genes, the control of transcription is paramount.
 This makes sense because only transcriptional control can
ensure that no unnecessary intermediates are synthesized.
 Until 50 years ago, the idea that genes could be switched on
and off was revolutionary.
 This concept was a major advance, and it came originally
from studies of how E. coli bacteria adapt to changes in the
composition of their growth medium.
 Many of the same principles apply to eukaryotic cells.
However, of gene regulation in higher organisms is
enormously complex.
 Regulatory DNA sequences
 Control of transcription is usually exerted at the step at which the process is
initiated.
 We saw that the promoter region of a gene binds the enzyme RNA polymerase
and correctly orients the enzyme to begin its task of making an RNA copy of
the gene.
 The promoters of both bacterial and eukaryotic genes include a transcription
initiation site, where RNA synthesis begins, plus a sequence of approximately
50 nucleotide pairs that extends upstream from the initiation site.
 This upstream region contains sites that are required for the RNA polymerase
to recognize the promoter, although they do not bind to RNA polymerase
directly.
 Instead, these sequences contain recognition sites for proteins that associate
with the active polymerase—sigma factor in bacteria or the general
transcription factors in eukaryotes.
 In addition to the promoter, nearly all genes, whether bacterial or eukaryotic,
have regulatory DNA sequences that are used to switch the gene on or off.
 Regulatory DNA sequences must be recognized by proteins
called transcription regulators to exert their effects.
 It is the binding of a transcription regulator to a regulatory DNA
sequence that acts as the switch to control transcription.
 Regulatory proteins that recognize a specific nucleotide
sequence because the surface of the protein fits tightly against
the surface features of the DNA double helix in that region.
 Because these surface features will vary depending on the
nucleotide sequence, different DNA-binding proteins will
recognize different nucleotide sequences.
 In most cases, the protein inserts into the major groove of the
DNA helix and makes a series of intimate molecular contacts
with the nucleotide pairs within the groove.
 Prokaryotic Gene Regulation
 The simplest and best understood examples of gene regulation occur in
bacteria.
 The genome of the bacterium E. coli consists of a single circular DNA
molecule of about 4.6 × 106 nucleotide pairs. This DNA encodes
approximately 4300 proteins, although only a fraction of these are
made at any one time. Bacteria regulate the expression of many of their
genes according to the food sources that are available in the
environment.
 For example, in E. coli, 5 genes code for enzymes that manufacture the
amino acid tryptophan.
 These genes are arranged in a cluster on the chromosome and are
transcribed from a single promoter as one long mRNA molecule; such
coordinately transcribed clusters are called operons.
 Although operons are common in bacteria, they are rare in eukaryotes,
where genes are transcribed and regulated individually.
Transcriptional Repressors: Trp Operon
 When tryptophan concentrations are low, the operon is transcribed; the
resulting mRNA is translated to produce a full set of biosynthetic enzymes,
which work in tandem to synthesize tryptophan.
 When tryptophan is abundant, the amino acid is imported into the cell and
shuts down production of the enzymes, which are no longer needed.
 Within the operon’s promoter is a short DNA sequence, called the operator,
that is recognized by a transcription regulator.
 When this regulator binds to the operator, it blocks access of RNA polymerase
to the promoter, preventing transcription of the operon and production of the
tryptophan-producing enzymes.
 The transcription regulator is known as the tryptophan repressor, and it is
controlled in an ingenious way: the repressor can bind to DNA only if it has
also bound several molecules of tryptophan.
 The binding of tryptophan causes a subtle change in its three-
dimensional structure so that the protein can bind to the
operator sequence.
 When the concentration of free tryptophan in the bacterium
drops, the repressor no longer binds to DNA, and the tryptophan
operon is transcribed.
 The repressor is thus a simple device that switches production of
a set of biosynthetic enzymes off according to the availability of
the end product of the pathway that the enzymes catalyze.
 Transcriptional Activators
 The tryptophan repressor, as its name suggests, is a
transcriptional repressor protein: in its active form, it
switches genes off, or represses them.
 Some bacterial transcription regulators do the opposite:
they switch genes on, or activate them.
 These transcriptional activator proteins work on
promoters that—in contrast to the promoter for the
tryptophan operon—are only not able to bind and position
RNA polymerase on their own.
 These poorly functioning promoters can be made fully
functional by activator proteins that bind nearby and
contact the RNA polymerase to help it initiate
transcription.
 Lac Operon
 Like the tryptophan repressor, activator proteins often have to interact
with a second molecule to be able to bind DNA.
 For example, the bacterial activator protein CAP has to bind cyclic AMP
(cAMP) before it can bind to DNA. Genes activated by CAP are
switched on in response to an increase in intracellular cAMP
concentration, which rises when glucose, the bacterium’s preferred
carbon source, is no longer available; as a result, CAP drives the
production of enzymes that allow the bacterium to digest other sugars.
 In many instances, the activity of a single promoter is controlled by two
different transcription regulators.
 The Lac operon in E. coli, for example, is controlled by both the Lac
repressor and the CAP activator.
 The Lac operon encodes proteins required to
import and digest the disaccharide lactose.
 In the absence of glucose, the bacterium
makes cAMP, which activates CAP to switch Lac Operon
on genes that allow the cell to utilize
alternative sources of carbon—including
lactose.
 It would be wasteful, however, for CAP to
induce expression of the Lac operon if
lactose itself were not present. Thus the Lac
repressor shuts off the operon in the absence
of lactose.
 This arrangement enables the control region
of the Lac operon to integrate two different
signals, so that the operon is highly
expressed only when two conditions are met:
glucose must be absent and lactose must be
present.
 When lactose is present AND glucose is
absent, the cell executes the appropriate
program—in this case, transcription of the
genes that permit the uptake and utilization
of lactose.
 Eukaryotic Gene Regulation
 Eukaryotes, too, use transcription regulators—both
activators and repressors—to regulate the expression
of their genes. The DNA sites to which eukaryotic gene
activators bind are termed enhancers, because their
presence dramatically enhances the rate of
transcription.
 Activator proteins could enhance transcription even
when they are bound thousands of nucleotide pairs
away from a gene’s promoter.
 They also work when bound either upstream or
downstream from the gene.
 The DNA between the enhancer and the promoter loops out to allow eukaryotic activator
proteins to influence directly events that take place at the promoter. The DNA thus acts as
a tether, allowing a protein that is bound to an enhancer—even one that is thousands of
nucleotide pairs away—to interact with the proteins in the vicinity of the promoter—
including RNA polymerase and the general transcription factors.
 Often, additional proteins serve to link the distantly bound transcription regulators to
these proteins at the promoter; the most important of these regulators is a large complex
of proteins known as Mediator.
 One of the ways in which activator proteins function is by aiding the assembly of the
general transcription factors and RNA polymerase to form a large transcription complex
at the promoter.
 Eukaryotic repressor proteins do the opposite: they decrease transcription by preventing
the assembly of the same protein complex.
 In addition to promoting—or repressing—the assembly of a
transcription initiation complex directly, eukaryotic
transcription regulators have an additional mechanism of action:
they attract proteins that modify chromatin structure and
thereby affect the accessibility of the promoter to the general
transcription factors and RNA polymerase.
 Eukaryotic DNA is packed into nucleosomes, which, in turn, are
folded into higher-order structures. So transcription regulators,
general transcription factors, and RNA polymerase should
somehow gain access to such DNA for transcription to occur.
 Nucleosomes can inhibit the initiation of transcription if they
are positioned over a promoter, because they physically block the
assembly of the general transcription factors or RNA polymerase
on the promoter.
 Such chromatin packaging may have evolved in part to prevent
leaky gene expression by blocking the initiation of transcription
in the absence of the proper activator proteins.
 In eukaryotic cells, activator and repressor proteins exploit
chromatin structure to help turn genes on and off.
 As we discussed, chromatin structure can be
altered by chromatin-remodeling complexes and
by enzymes that covalently modify the histone
proteins that form the core of the nucleosome.
 Many gene activators take advantage of these
mechanisms by recruiting such chromatin-
modifying proteins to promoters. For example,
the recruitment of histone acetyltransferases
promotes the attachment of acetyl groups to
selected lysines in the tail of histone proteins.
 This modification alters chromatin structure,
allowing greater accessibility to the underlying
DNA; moreover, the acetyl groups themselves
attract proteins that promote transcription,
including some of the general transcription
factors.
 Likewise, gene repressor proteins can modify
chromatin in ways that reduce the efficiency of
transcription initiation. For example, many
repressors attract histone deacetylases—enzymes
that remove the acetyl groups from histone tails,
thereby reversing the positive effects that
acetylation has on transcription initiation.
 In contrast, the simplest changes in gene
expression in both eukaryotes and bacteria are
often only transient.
 Because eukaryotic transcription regulators can
control transcription initiation when bound to
DNA many base pairs away from the promoter,
the nucleotide sequences that control the
expression of a gene can be spread over long
stretches of DNA.
 In animals and plants, it is not unusual to find
the regulatory DNA sequences of a gene dotted
over tens of thousands of nucleotide pairs,
although much of the intervening DNA serves
as “spacer” sequence and is not directly
recognized by the transcription regulators.
 Most eukaryotic transcription regulators work as
part of a “committee” of regulatory proteins, all
of which are necessary to express the gene in the
right place, in the right cell type, in response to
the right conditions, at the right time, and in the
required amount.
 The term combinatorial control refers to the
way that groups of transcription regulators work
together to determine the expression of a single
gene.
 In eukaryotes, the regulatory inputs have been amplified, and a
typical gene is controlled by dozens of transcription regulators.
 These help assemble chromatin-remodeling complexes, histone-
modifying enzymes, RNA polymerase, and general transcription
factors via the multiprotein Mediator complex.
 In addition to being able to switch individual genes on and off,
all cells—whether prokaryote or eukaryote—need to coordinate
the expression of different genes.
 When an eukaryotic cell receives a signal to divide, for example, a
number of unexpressed genes are turned on together to set in
motion the events that lead eventually to cell division.
 As discussed earlier, one way in which bacteria coordinate the
expression of a set of genes is by having them clustered together
in an operon under the control of a single promoter.
 Such clustering is not seen in eukaryotic cells, where each gene is
transcribed and regulated individually.
 Even though control of gene expression is
combinatorial, the effect of a single transcription
regulator can still be decisive in switching any
particular gene on or off, simply by completing the
combination needed to activate or repress that gene.
 The same protein can complete the combination for
several different genes. As long as different genes
contain regulatory DNA sequences that are recognized
by the same transcription regulator, they can be
switched on or off together, as a coordinated unit.
 An example of such coordinated regulation in humans
is seen with the cortisol receptor protein.
 In order to bind to regulatory sites in
DNA, transcription regulator cortisol
receptor protein must first form a
complex with a molecule of cortisol.
 In response to cortisol, liver cells
increase the expression of many genes,
one of which encodes the enzyme
tyrosine aminotransferase.
 All these genes are regulated by the
binding of the cortisol–receptor
complex to a regulatory sequence in
the DNA of each gene.
 When the cortisol concentration
decreases again, the expression of all
of these genes drops to its normal
level.
 In this way, a single transcription
regulator can coordinate the
expression of many different genes.
 The ability to switch many different genes on or off using a limited
number of transcription regulators is not only useful in the day-to-day
regulation of cell function.
 It is also one of the means by which eukaryotic cells diversify into
particular types of cells during embryonic development.
 A striking example is the development of muscle cells. A mammalian
skeletal muscle cell is distinguished from other cells by the production
of a large number of characteristic proteins, such as the muscle-specific
forms of actin and myosin that make up the contractile apparatus as
well as the receptor proteins and ion channel proteins in the plasma
membrane that make the muscle cell sensitive to nerve stimulation.
 The genes encoding these muscle-specific proteins are all switched on
coordinately as the muscle cell differentiates.
 Studies of developing muscle cells in culture have identified a small
number of key transcription regulators, expressed only in potential
muscle cells, that coordinate muscle-specific gene expression and are
thus crucial for muscle-cell differentiation.
 This set of regulators activates the transcription of the genes that code
for muscle-specific proteins by binding to specific DNA sequences
present in their regulatory regions.
 Some transcription regulators can even convert one
specialized cell type to another. For example, when the
gene encoding the transcription regulator MyoD is
artificially introduced into fibroblasts cultured from skin
connective tissue, the fibroblasts form musclelike cells.
 It appears that the fibroblasts, which are derived from the
same broad class of embryonic cells as muscle cells, have
already accumulated many of the other necessary
transcription regulators required for the combinatorial
control of the muscle-specific genes, and that addition of
MyoD completes the unique combination required to
direct the cells to become muscle.
 This type of reprogramming
can produce even more
dramatic effects.
 For example, a set of nerve-
specific transcription
regulators, when artificially
expressed in cultured liver
cells, can convert them into
functional neurons.
 Such dramatic results suggest
that it may someday be
possible to produce in the
laboratory any cell type for
which the correct
combination of transcription
regulators can be identified.
 We have seen that, in some cases, one type of differentiated cell can be
experimentally converted into another type by the artificial expression
of specific transcription regulators.
 Even more surprising, transcription regulators can reprogramme
various differentiated cells into pluripotent stem cells that are capable
of giving rise to all the specialized cell types in the body, much like the
embryonic stem (ES) cells.
 Using a defined set of transcription regulators, cultured mouse
fibroblasts have been reprogrammed to become induced pluripotent
stem (iPS) cells—cells that look and behave like the pluripotent ES
cells that are derived from embryos.
 The approach was quickly adapted to produce iPS cells from a variety of
specialized cell types, including cells taken from humans. Such human
iPS cells can then be directed to generate a population of differentiated
cells for use in the study or treatment of disease.
 We have seen that a small number of transcription
regulators can control the expression of whole sets
of genes and can even convert one cell type into
another.
 But an even more stunning example of the power
of transcriptional control comes from studies of
eye development in Drosophila.
 In this case, a single “master” transcription
regulator called Ey could be used to trigger the
formation of not just a single cell type but a whole
organ.
 In the laboratory, the Ey gene can be artificially
expressed in fruit fly embryos in cells that would
normally give rise to a leg. When these modified
embryos develop into adult flies, some have an eye
in the middle of a leg.
• Ey functions like any other transcription regulator, controlling the expression of
multiple genes by binding to DNA sequences in their regulatory regions.
• Some of the genes controlled by Ey encode additional transcription regulators
that, in turn, control the expression of other genes.
• In this way, the action of a single transcription regulator can produce a cascade of
regulators that, working in combination, lead to the formation of an organized
group of many different types of cells.
 Cell memory
 Once a cell in a multicellular organism becomes committed to differentiate into
a specific cell type, the choice of fate is generally maintained through
subsequent cell divisions.
 Some highly specialized cells, including skeletal muscle cells and neurons,
never divide again once they have differentiated—that is, they are terminally
differentiated.
 But many other differentiated cells—such as fibroblasts, smooth muscle cells,
and liver cells—will divide many times in the life of an individual.
 When they do, these specialized cell types give rise only to cells like themselves:
smooth muscle cells do not give rise to liver cells, nor liver cells to fibroblasts.
 For a proliferating cell to maintain its identity—a property called cell
memory—the patterns of gene expression responsible for that identity must
be remembered and passed on to its daughter cells through all subsequent cell
divisions.
 This means that the changes in gene expression, which are often triggered by a
transient signal, must be remembered by the cell. This phenomenon of cell
memory is a prerequisite for the creation of organized tissues and for
the maintenance of stably differentiated cell types.
 Cells have several ways of ensuring that their daughters “remember” what
kind of cells they are. One of the simplest and most important is through
a positive feedback loop, where a master transcription regulator
activates transcription of its own gene, in addition to that of other cell-
type–specific genes.
 Each time a cell divides the regulator is distributed to both daughter
cells, where it continues to stimulate the positive feedback loop. The
continued stimulation ensures that the regulator will continue to be
produced in subsequent cell generations.
 The Ey protein discussed earlier functions in such a positive feedback
loop. Positive feedback is crucial for establishing the “self-sustaining”
circuits of gene expression that allow a cell to commit to a particular
fate—and then to transmit that information to its progeny.
 Epigenetics
 Epigenetic mechanism is another way of reinforcing cell identity.
 DNA methylation, one of the epigenetic mechanism, involves
cytosine methylation that turns off genes by attracting proteins
that bind to methylated cytosines and block gene transcription.
 DNA methylation patterns are passed on to progeny cells by the
action of an enzyme that copies the methylation pattern on the
parent DNA strand to the daughter DNA strand as it is
synthesized.
 Another epigenetic mechanism for inheriting gene
expression patterns involves the modification of histones.
 When a cell replicates its DNA, each daughter double helix
receives half of its parent’s histone proteins, which contain
the covalent modifications of the parent chromosome.
 Enzymes responsible for these modifications may bind to
the parental histones and confer the same modifications to
the new histones nearby.
 This cycle of modification reestablishes the pattern of
chromatin structure found in the parent chromosome.
 Because all of these cell-memory mechanisms transmit
patterns of gene expression from parent to daughter
cell without altering the actual nucleotide sequence of
the DNA, they are considered to be forms of
epigenetic inheritance.
 Such epigenetic changes play an important part in
controlling patterns of gene expression, allowing
transient signals from the environment to be
permanently recorded by our cells.
Post-Transcriptional Control of Gene Expression
 We have seen that transcription regulators control gene
expression by promoting or hindering the transcription of
specific genes. The vast majority of genes in all organisms are
regulated in this way.
 But many additional points of control can come into play later in
the pathway from DNA to protein, giving cells a further
opportunity to regulate the amount or activity of the gene
products that they make.
 These post-transcriptional controls, which operate after
transcription has begun, play a crucial part in regulating the
expression of almost all genes. Examples include:
 Alternative RNA splicing allows different forms of a protein,
encoded by the same gene, to be made in different tissues.
 Post-translational modifications of a protein can regulate its
concentration and activity.
 The more time an mRNA persists in the cell before it is
degraded, the more protein it will produce.
 In bacteria, most mRNAs last only a few minutes before being
destroyed. This instability allows a bacterium to adapt quickly to
environmental changes. Eukaryotic mRNAs are generally more
stable.
 Most eukaryotic mRNAs, however, have half-lives of less than 30
minutes, and the most short-lived are those that encode proteins
whose concentrations need to change rapidly based on the cell’s
needs, such as transcription regulators.
 Whether bacterial or eukaryotic, an mRNA’s lifetime is dictated
by specific nucleotide sequences within the untranslated regions
(UTR) that lie both upstream and downstream of the protein-
coding sequence. These sequences often harbor binding sites for
proteins that are involved in RNA degradation or blocking of
translation.
 Some of these sequences control how often or how efficiently the mRNA will be
translated into protein. These sequences control translation initiation.
 Bacterial mRNAs contain a short ribosome-binding sequence located a few
nucleotide pairs upstream of the AUG codon where translation begins. This
binding sequence forms base pairs with the RNA in the small ribosomal
subunit, correctly positioning the initiating AUG codon within the ribosome.
 Because this interaction is needed for efficient translation initiation, it
provides an ideal target for translational control. By blocking—or exposing—
the ribosome-binding sequence, the bacterium can either inhibit—or
promote—the translation of an mRNA.
 Eukaryotic mRNAs possess a 5′ cap that helps guide the ribosome to the first
AUG, the codon where translation will start.
 Eukaryotic repressor proteins can inhibit translation initiation by binding to
specific nucleotide sequences in the 5′ untranslated region of the mRNA,
thereby preventing the ribosome from finding the first AUG—a mechanism
similar to that in bacteria.
 When conditions change, the cell can inactivate the repressor to initiate
translation of the mRNA.
 Regulatory RNAs
 In addition to the mRNAs, which code for proteins,
noncoding RNAs have various functions.
 Some have key structural and catalytic roles, particularly in
protein synthesis by ribosomes (tRNA and rRNA).
 Some others have important roles in regulating gene
expression and are therefore referred to as regulatory
RNAs.
 There are at least three major types of regulatory RNAs:
 microRNAs,
 small interfering RNAs,
 long noncoding RNAs.
 miRNA
 MicroRNAs, or miRNAs, are tiny RNA
molecules that control gene expression by
base-pairing with specific mRNAs and
reducing both their stability and their
translation into protein.
 Mature, functional miRNA molecule, which
is only about 22 nucleotides in length.
 This small but mature miRNA is packaged
with specialized proteins to form an RNA-
induced silencing complex (RISC), which
patrols the cytoplasm in search of mRNAs
that are complementary to the bound
miRNA molecule.
 Once a target mRNA forms base pairs with
an miRNA, it is either destroyed
immediately by a nuclease present within
the RISC or its translation is blocked.
 siRNA
 Some of the same components that process
and package miRNAs also play another
crucial part in the life of a cell: they serve as
a powerful cell defense mechanism.
 In this case, the system is used to eliminate
“foreign” RNA molecules—in particular, the
double-stranded RNAs produced by many
viruses and transposable genetic elements.
 siRNA resembles certain aspects of the
adaptive immune responses of vertebrates;
in both cases, an invading pathogen elicits
the production of molecules—either siRNAs
or antibodies— that are custom-made to
inactivate the specific invader and thereby
protect the host.
 lncRNA
 Long noncoding RNAs are a class of RNA molecules that are
more than 200 nucleotides in length.
 With few exceptions, their roles in the biology of the organism
are not entirely clear.
 One of the best understood of the long noncoding RNAs is Xist.
This enormous RNA molecule, some 17,000 nucleotides long, is a
key player in X inactivation—the process by which one of the
two X chromosomes in the cells of female mammals is
permanently silenced.
 Early in development, Xist is produced by only one of the X
chromosomes in each female nucleus. The transcript then “sticks
around,” coating the chromosome and presumably attracting the
enzymes and chromatin remodeling complexes that promote the
formation of highly condensed heterochromatin.
 Other long noncoding RNAs may promote the silencing of
specific genes in a similar manner.
 Some long noncoding RNAs arise from protein-coding regions of
the genome, but are transcribed from the “wrong” DNA strand.
Some of these antisense transcripts are known to bind to the
mRNAs produced from that DNA segment, regulating their
translation and stability.
 Regardless of how the various long noncoding RNAs operate—or
what exactly they do—the discovery of this large class of RNAs
reinforces the idea that a eukaryotic genome is densely packed
with information that provides not only an inventory of the
molecules and structures every cell must make, but a set of
instructions for how and when to assemble these parts to guide
the growth and development of a complete organism.