https://cz.pinterest.com/taolog/life-science/
Complicated network of many different
factors which work in dependency to space
and time
 Products of the same gene have different
functions in different tissues
 Different genes coding similar products
are expressed in different phases of
ontogenetic development
Constraining codes. Regulatory
elements within protein-coding
regions (such as transcription
factor binding) can influence
codon choice and amino acid
preference that are independent
of protein structure or function.
R J Weatheritt, and M M Babu Science 2013;342:1325-1326
cis = on the same molecule
promoter
trans = on different molecule
 Transcription depends on the presence of
activated transcription factors
 it is TURN ON, if they are available
 it is TURN OFF, if they are not available
enhancer promoter
binding site for DNA
(trans)-
activating
domains
They have mostly positive, but also negative
effect on transcription
Transcription factors without the binding site
for DNA bind to the DNA through other
transcription factors
Activators of the
transcription factors
bind to the activating
domains
activators
 They accelerate speed of pre-initiation
complex formation
 They stimulate transcription after initiation
complex formation
 They change conformation of transcription
factor
They influence transcription initiation
activator
promoter
transcription factor
direct influence
co-activatorindirect influence
activator
promotor
transcription factor
co-activator
direct influence
indirect influence
Transcriptional network of
MITF-M in melanoma. The
picture shows upstream
MITF-M activators and main
downstream transcription
targets. The blue boxes
indicate transcriptional
coactivators and red boxes
denote two transcription
factors probably having
more important role for the
MITF-M expression in
melanoma. Broken lines
indicate that not all MITF-M
targets may be coactivated
by indicated epigenetic
coactivators.
Jiri Vachtenheim and Lubica Ondrušova (2013). MITF: A Critical Transcription Factor in Melanoma
Transcriptional Regulatory Network, Recent Advances in the Biology, Therapy and Management of
Melanoma, Dr. Lester Davids (Ed.), InTech, DOI: 10.5772/55191.
CREB
CBP/
p300
cAMP
SREBP
cholesterol
MyoD
muscle
differentiation
intracellular
receptors
steroid
thyroid
gland
AP1
growth
stimulation
STATfaktors
p53
NF-κB
interferons
cytokines stop cell growth
cytokines
 They are far hundreds or thousands
nucleotides from promoter
 In cis position, upstream or downstream of
gene
 Mechanisms of the enhancers acts through the
transcription factors; the result of this process
is establishment of RNA polymerase to active
state
Regulatory sequences which turn up or turn down the
transcription
enhancer promoter
mRNA
enhancer
promotor
bend induced protein
activated
transcription factor
RNA polymerase
signal IS x IS NOT present
level of activator × level of represor
place of expression – tissue specificity
period of expression - ontogenesis
A
nucleosome
X
transcription
activator X
transcription
activator A
transcription activation
Transcription activation is coupled with change of chromatin structure
doi:10.1038/nrm1680
 Change of conformation induced by ligand
 Change of conformation after removing of
inhibitory protein
 Change of conformation by phosphorylation
 phosphorylation by proteinkinase
 dephosphorylation by phosphatase
 Stabilisation of transcription factor active
conformation against its degradation
Joseph A. D'Alessio, J.A., Wright, K.J. and Tjian, R. (2009): Shifting Players
and Paradigms in Cell-Specific Transcription. Cell 36, December 24, 924-931
1) Sequence-specific activators (green) bind proximal
(PE) and distal (DE) enhancer elements
Joseph A. D'Alessio, J.A., Wright, K.J. and Tjian, R. (2009): Shifting Players
and Paradigms in Cell-Specific Transcription. Cell 36, December 24, 924-931
2) It recruits basal factor TFIID (yellow) to the core
promoter
Joseph A. D'Alessio, J.A., Wright, K.J. and Tjian, R. (2009): Shifting Players
and Paradigms in Cell-Specific Transcription. Cell 36, December 24, 924-931
3) recruit chromatin remodelling complexes such as
SWI/SNF (orange), co-activators including Mediator
(MED, blue), and TFIIA and TFIIB (purple).
Joseph A. D'Alessio, J.A., Wright, K.J. and Tjian, R. (2009): Shifting Players
and Paradigms in Cell-Specific Transcription. Cell 36, December 24, 924-931
4) The TFIID/TFIIA/TFIIB heterotrimer sequentially recruits
TFIIE, TFIIF, PolII (red), and TFIIH (purple), allowing for
promoter escape and productive transcriptional
elongation
D'Alessio et al. (2009): Cell 36, December 24, 924-931
Embryonic stem cells have a „standard“ set of
transcription factors
D'Alessio et al. (2009): Cell 36, December 24, 924-931
Myotubes may replace TFIID with a novel complex of
TRF and TAF3, they have not Med
D'Alessio et al. (2009): Cell 36, December 24, 924-931
Neurons have new complex BAF, the other factors are
not known
D'Alessio et al. (2009): Cell 36, December 24, 924-931
Spermatocytes have elevated levels of TRF2 and of the
TAF7 paralog TAF7l (lime), which may or may not be a
component of an altered TFIID
D'Alessio et al. (2009): Cell 36, December 24, 924-931
Ovarian cells have elevated levels of TRF3 and of an altered
TFIID containing one or more subunits of the TAF4 paralog,
TAF4b (tan). Constitutions of Med and BAF are not known.
 The genes which are not expressed in
given to developmental stage are
methylated
 DNA-metylase
5-metylcytosine
N
H
N
O
NH2
CH3
Genomic imprinting is a genetic phenomenon by which
certain genes are expressed in a parent-of-origin-specific
manner. It is an inheritance process independent of the
classical Mendelian inheritance.
Imprinted alleles are silenced such that the genes are either
expressed only from the non-imprinted allele inherited from
the mother (e.g. H19 or CDKN1C), or in other instances from
the non-imprinted allele inherited from the father (e.g. IGF-2).
The allele coding for insulin IGF-2 in mouse is expressed if it
is coming from father, not from mother.
This phenomenon is done by methylation the allele in
oocytes.
The process of methylation is irreversible.
• The ratio of individual transcription factors control the expression of
particular genes
• Well-studied in Drosophila melanogaster embryo
http://www.sdbonline.org/sites/fly/lewheld/id42.htm
http://what-when-how.com/molecular-biology/pair-rule-genes-
molecular-biology/
 Signals for activation of transcription are
extracellular
 Intracellular signals follow the extracellular
signals
The cell is complex regulated system which
reacts to external signals by changes in gene
expression. The changes are on the levels of
transcription, translational, posttranscriptional,
and posttranslational
Signal is a physical factor for transmission
information
Signal molecule is a small molecule or
macromolecule which has function of
a signal
Signal molecules
 extracelullar: originated outside cell; receptor
and ligand
 intracelullar: originated inside cell, hormones,
growth factors, neurotransmitters, cAMP, Gproteins,
RAS protein
change of
conformation
signal
receptor
membrane
Induction of enzymatic
activity in cell
Reaction of the cell
to signal
Transmission of signal from cell, which is
originator of the signal, to receptor of
recipient cell
Contact depending signalisation
Paracrine signalisation
Endocrine signalisation
Gap junction signalisation
Autocrine signalisation
signaling cell target cell
ligand
receptor
signaling cell
target cells
Blood stream
Transmission of small molecules = Ca2+, cAMP
Signaling cell is also target cell
Extracellular and intracellular signaling
create formation of signal molecules
cascade, in which the molecules transfer
information from one to another
 first messenger
 second messenger
The second messengers amplify the
original (extracellular) signal
Cell Membrane
Nucleus
Scaffold
protein
Modulator
protein
Anchoring
protein
Transcription
 serine/threonine proteinkinases
 tyrosine proteinkinases
 mitogene activated protein kinases (MAPK)
 adenylatcyclases
 guanylatcyclases
 phospholipases
 phosphatases
 Hormones derived from amino acids =
adrenaline, thyroxin, etc.
 Peptide hormones = insulin, glucagon, ...
 Steroid hormones and glucocorticoids
 „Tissue“ hormones = serotonin, gastrin,
erythropoietin, etc.
 G-protein = heterotrimer composed from Gα, Gβ and
Gγ subunit
 Gα-subunit possesses GTPase activity, in non-active
state binds GDP
 Binding of ligands (e.g., some hormones – serotonin,
epinefrin,…) causes exchange of GDP to GTP on Gα-
subunit
 Gα-subunit disociates from Gβ/γ subunits and both
parts activate other enzymes
 After a few seconds, Gα-subunit hydrolises GTP on
GDP  recreation of heterotrimer
Physiological Reviews Published 1 April 2015 Vol. 95 no. 2, 377-404 DOI: 10.1152/physrev.00015.2014
Nature Reviews Cancer 7, 79-94 (February 2007) doi:10.1038/nrc2069
Nature Reviews Cancer 7, 79-94 (February 2007) doi:10.1038/nrc2069
 Receptors for steroid hormones, thyroxine, retinoic
acid and vitamin D
 Receptors occurs either in cytoplasm on in nucleus
 Ligand (signal) entre to cell, where it bind on
receptor, which represents transcription factor, as
well
Steroid Hormone Receptors (SHR) act as
hormone dependent nuclear transcription
factors.Upon entering the cell by passive
diffusion, the hormone (H) binds the receptor,
which is subsequently released from heat
shock proteins, and translocates to the nucleus.
There, the receptor dimerizes, binds specific
sequences in the DNA, called Hormone
Responsive Elements or HREs, and recruits a
number of coregulators that facilitate gene
transcription.
This latter step can be modulated by receptor
antagonists like tamoxifen (T), and cellular
signalling pathways.
Legend
1. hormone binding
2. chaperone interaction
3. nuclear translocation
4. receptor dimerization
5. DNA binding
6. putative membrane-bound receptors
7. coregulator recruitment
8. transcription
9. proteasomal degradation
10. modulation by cellular signalling pathways
11. antagonist resistance