Genetics 15
HC 12-13
15.1
Gene regulation is in place so that gene expression can be controlled at high or low levels.
For this sake, genes are expressed in an accurate pattern during various developmental
stages in life; during embryonic development, certain genes are on with need to be switched
off later. It also enables differences among distinct cell types, it expresses and regulates
genes in different ways, which is why muscle and nerve cells, though they contain the same
genes, look phenotypically so distinct. Also, with regard to homeostasis is gene regulation
needed, to achieve stability in response to changes in the environment like diet or stress.
Gene regulation happens mostly during transcription, but in eukaryotes it can also take
place during RNA-processing, translation or post-translation.
Transcription factors (TFs) are a category of proteins that influence the ability of RNA pol to
transcribe a certain gene. There are two types:
- General transcription factors: required for the binding of RNA pol to core promoter
and its progression to elongation
- Regulatory transcription factors: regulate the rate of transcription of nearby genes
and influence the ability of RNA pol to initiate transcription. They typically recognise
cis-acting elements/control elements/response elements/regulatory elements. So,
they bond to the above and thereby influence rate of transcription; if a regulatory TF
binds to an enhancer, it is an activator and increases rate. Conversely, if it binds to a
silencer it is a repressor and decreases the rate.
Nevertheless, it is not black and white, a combination of many factors and elements
together determine the expression of a gene; combinatorial control. Think about more than
one activator/repressor have one effect, the function of activators/repressors may be
influenced, the nucleosome arrangement may be altered, or DNA methylation may inhibit
transcription. Moreover, a gene is not switched on or off, but rather fluctuates from the
many signals it receives, it is balanced.
Apparently, all TFs have distinct regions within the protein with a special function; domains.
There is one domain that enables the binding to DNA major groove. One domain acts as a
transcription activation domain and the other domain as a binding site for small effector
molecules. If domains tend to be the same between species, that domain has evolutionary
proved essential and was thus conserved during evolution. Once domains have a similar
structure in proteins of different origins, they are termed motifs. So, a series of contiguous
secondary structures of which the domain consists. Two identical TFs may come together to
form a homodimer and then exert a function, or two different TFs, heterodimer, can do the
same. The dimerization proves vital to modulate their function.
TF as activator binds to enhancer up-regulates transcription. TF as repressor that binds to
silencer down-regulate transcription. Also, regulatory elements or orientation-independent
or bidirectional, so they can function in forward and reverse orientation. As long as a loop
can be formed so as to be able to reach GTF/TSS to actively increase transcription.
The net effect of regulatory TFs is to influence the ability of RNA pol to transcribe a gene.
However, there is no direct binding of regulatory TFs to RNA pol, there are three pathways:
- Regulation via TFIID: TF bind to regulatory element and then influence TFIID.
Activator proteins promote TFIID initiation by letting it bind to TATA-box; sometimes
, there are coactivators needed which have a transactivation domain that recruits RNA
pol. In contrast, repressor proteins inhibit the binding of TFIID to TATA-box by
binding themselves to a silencer.
- Regulation via mediator: protein complex that mediates interaction between RNA
pol and regulatory TFs. It does so by mediating the phosphorylation of the CTD of
RNA pol, the critical step towards elongation. An activator may bind to enhancer,
through which mediator is activated and phosphorylation occurs; a repressor may
bind to a silencer and have the inverse effect.
- Changes in chromatin structure: regulatory TFs may recruit proteins that affect
nucleosome positioning and composition.
The exact function of regulatory TFs can be modulated in three ways:
- Binding of small effector molecule/hormone: one such example is a category that
reacts to steroid hormones, the regulatory TF is called a steroid receptor. Steroid
hormones act as signalling molecules, like glucocorticoid (nutrient metabolism) that
enters the cytosol through diffusion. It there binds to glucocorticoid receptor,
whereby the previously bound HSP90 proteins are released and a nuclear
localisation signal is exposed (NLS). This directs the protein/receptor into the
nuclear, subsequent to the formation of two such proteins; so, they enter nucleus as
homodimer. In the nucleus it binds with a specific enhancer DNA sequence (the
glucocorticoid receptor element, GRE) where after the transcription of the adjacent
gene is activated. GRE is found in many places, so the hormone affects a number of
genes.
- Protein-protein interactions, like the formation of a homo- or heterodimer that
together can bind to enhancer and activate a gene.
- Covalent modification: an extracellular signalling molecule binds to a receptor
outside the cell, whereby it activates a cell response. In the case of the cAMP
response element-binding (CREB) protein, it activates cAMP as a second messenger
(the primary one was the extracellular signalling molecule). The primary messenger
binds to plasma membrane receptor activates G protein activates adenylyl
cyclase changes ATP into cAMP binds & activates kinase A phosphorylates
CREB protein in the nucleus CREB can bind to CREB-binding protein (CBP)
activates RNA pol and transcription.
15.2
ATP-dependent chromatin remodelling changes the position of one or a few nucleosomes or
even affect chromatin structure over large distances. Chromatin thus, alternates between
two conformations:
- Closed conformation: chromatin is tightly packed, so transcription is difficult or
impossible
- Open conformation: chromatin highly extended, easily accessible, so transcription
can take place.
Chromatin is dynamic, and several molecular mechanisms can change its form. One such
way is through ATP-dependent chromatin remodelling, whereby energy from ATP hydrolysis
is used to change position/composition of nucleosomes. The complexes that carry this out
have a catalytic ATPase subunit known as DNA translocase. In greater detail, such complexes
either change the physical location of nucleosomes, shifts in spaces whereby new/longer
DNA stretches become accessible. Or they may simply evict octamers from the DNA,
HC 12-13
15.1
Gene regulation is in place so that gene expression can be controlled at high or low levels.
For this sake, genes are expressed in an accurate pattern during various developmental
stages in life; during embryonic development, certain genes are on with need to be switched
off later. It also enables differences among distinct cell types, it expresses and regulates
genes in different ways, which is why muscle and nerve cells, though they contain the same
genes, look phenotypically so distinct. Also, with regard to homeostasis is gene regulation
needed, to achieve stability in response to changes in the environment like diet or stress.
Gene regulation happens mostly during transcription, but in eukaryotes it can also take
place during RNA-processing, translation or post-translation.
Transcription factors (TFs) are a category of proteins that influence the ability of RNA pol to
transcribe a certain gene. There are two types:
- General transcription factors: required for the binding of RNA pol to core promoter
and its progression to elongation
- Regulatory transcription factors: regulate the rate of transcription of nearby genes
and influence the ability of RNA pol to initiate transcription. They typically recognise
cis-acting elements/control elements/response elements/regulatory elements. So,
they bond to the above and thereby influence rate of transcription; if a regulatory TF
binds to an enhancer, it is an activator and increases rate. Conversely, if it binds to a
silencer it is a repressor and decreases the rate.
Nevertheless, it is not black and white, a combination of many factors and elements
together determine the expression of a gene; combinatorial control. Think about more than
one activator/repressor have one effect, the function of activators/repressors may be
influenced, the nucleosome arrangement may be altered, or DNA methylation may inhibit
transcription. Moreover, a gene is not switched on or off, but rather fluctuates from the
many signals it receives, it is balanced.
Apparently, all TFs have distinct regions within the protein with a special function; domains.
There is one domain that enables the binding to DNA major groove. One domain acts as a
transcription activation domain and the other domain as a binding site for small effector
molecules. If domains tend to be the same between species, that domain has evolutionary
proved essential and was thus conserved during evolution. Once domains have a similar
structure in proteins of different origins, they are termed motifs. So, a series of contiguous
secondary structures of which the domain consists. Two identical TFs may come together to
form a homodimer and then exert a function, or two different TFs, heterodimer, can do the
same. The dimerization proves vital to modulate their function.
TF as activator binds to enhancer up-regulates transcription. TF as repressor that binds to
silencer down-regulate transcription. Also, regulatory elements or orientation-independent
or bidirectional, so they can function in forward and reverse orientation. As long as a loop
can be formed so as to be able to reach GTF/TSS to actively increase transcription.
The net effect of regulatory TFs is to influence the ability of RNA pol to transcribe a gene.
However, there is no direct binding of regulatory TFs to RNA pol, there are three pathways:
- Regulation via TFIID: TF bind to regulatory element and then influence TFIID.
Activator proteins promote TFIID initiation by letting it bind to TATA-box; sometimes
, there are coactivators needed which have a transactivation domain that recruits RNA
pol. In contrast, repressor proteins inhibit the binding of TFIID to TATA-box by
binding themselves to a silencer.
- Regulation via mediator: protein complex that mediates interaction between RNA
pol and regulatory TFs. It does so by mediating the phosphorylation of the CTD of
RNA pol, the critical step towards elongation. An activator may bind to enhancer,
through which mediator is activated and phosphorylation occurs; a repressor may
bind to a silencer and have the inverse effect.
- Changes in chromatin structure: regulatory TFs may recruit proteins that affect
nucleosome positioning and composition.
The exact function of regulatory TFs can be modulated in three ways:
- Binding of small effector molecule/hormone: one such example is a category that
reacts to steroid hormones, the regulatory TF is called a steroid receptor. Steroid
hormones act as signalling molecules, like glucocorticoid (nutrient metabolism) that
enters the cytosol through diffusion. It there binds to glucocorticoid receptor,
whereby the previously bound HSP90 proteins are released and a nuclear
localisation signal is exposed (NLS). This directs the protein/receptor into the
nuclear, subsequent to the formation of two such proteins; so, they enter nucleus as
homodimer. In the nucleus it binds with a specific enhancer DNA sequence (the
glucocorticoid receptor element, GRE) where after the transcription of the adjacent
gene is activated. GRE is found in many places, so the hormone affects a number of
genes.
- Protein-protein interactions, like the formation of a homo- or heterodimer that
together can bind to enhancer and activate a gene.
- Covalent modification: an extracellular signalling molecule binds to a receptor
outside the cell, whereby it activates a cell response. In the case of the cAMP
response element-binding (CREB) protein, it activates cAMP as a second messenger
(the primary one was the extracellular signalling molecule). The primary messenger
binds to plasma membrane receptor activates G protein activates adenylyl
cyclase changes ATP into cAMP binds & activates kinase A phosphorylates
CREB protein in the nucleus CREB can bind to CREB-binding protein (CBP)
activates RNA pol and transcription.
15.2
ATP-dependent chromatin remodelling changes the position of one or a few nucleosomes or
even affect chromatin structure over large distances. Chromatin thus, alternates between
two conformations:
- Closed conformation: chromatin is tightly packed, so transcription is difficult or
impossible
- Open conformation: chromatin highly extended, easily accessible, so transcription
can take place.
Chromatin is dynamic, and several molecular mechanisms can change its form. One such
way is through ATP-dependent chromatin remodelling, whereby energy from ATP hydrolysis
is used to change position/composition of nucleosomes. The complexes that carry this out
have a catalytic ATPase subunit known as DNA translocase. In greater detail, such complexes
either change the physical location of nucleosomes, shifts in spaces whereby new/longer
DNA stretches become accessible. Or they may simply evict octamers from the DNA,
