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Dr. Shataha S. Jumaah/Lecturer _____________________________________________ Genetics – 2nd /2nd Semester
[email protected] https://tiu.edu.iq/
2020 - 2021
TIU - Faculty of Science Medical Analysis Department
The term has evolved to include any process that alters gene activity without
changing the DNA sequence, and leads to modifications that can be transmitted to
daughter cells.
Study of heritable phenotype changes that do not involve alterations in the DNA
sequance.
The Greek prefix epi "over, outside of, around“ in epigenetics means features that are
"on top of" or "in addition to" the traditional genetic basis for inheritance.
Describe any heritable phenotypic change.
•In eukaryotes, epigenetic control can determine whether a gene is switched on
or off -i.e. whether the gene is expressed (transeribed and translated) or not.
•
•Epigenetic changes to gene expression play a role in lots of normal cellular
processes and can also occur in response to changes in the environment – e.g.
pollution and availability of food.
•Organisms inherit their DNA base sequence from their parents.
•This means that the expressions of some genes in offspring can be affected by environmental
changes that affected their parents or grandparents.
Epigenetic changes in some plants in response to drought (deficiency) have been shown to be
passed on the later generations
• There are sevral epigenetic mechanisms used to control gene expressions.
1. DNA Methylation
2. Histone modification
3. Non-coding RNA
• Increased methylation of DNA Methylation is when a methyl group (an
example of an epigenetic mark) is attached to the DNA coding for a gene.
The group always attaches at a CpG site, which is where a cytosine and
guanine base are next to each other in the DNA (linked by a
phosphodiester bond). Increased methylation changes the DNA structure
so that the transcriptional machinery (enzymes, etc,) can't interact with
the gene - so the gene is not expressed (i.e. it's switched of), pho acer
• Histones are proteins that DNA wraps around to form chromatin, which makes up
chromosomes. Chromatin can be highly condensed or less condensed. How condensed
it is affects the accessibility of the DNA and whether or not it can be transcribed.
•
• When histones are acegylated, the chromatin is less condensed.
• This means that the transcriptional machinery can access the DNA, allowing genes to
he transcribed. When acetyl groups are removed from the histones, the chromatin
becomes highly condensed and genes in the DNA can't be transcribed because the
transcriptional machinery can't physically access them. Histone deacetylase (HDAC )
enzymes are responsible for removing of Acetyl groups.
Your DNA is used as instructions for making coding and non-coding RNA.
Coding RNA is used to make proteins. Non-coding RNA helps control gene
expression by attaching to coding RNA, along with certain proteins, to break
down the coding RNA so that it cannot be used to make proteins. Non-
coding RNA may also recruit proteins to modify histones to turn genes “on”
or “off.”
• Epigenetics can play a role in the development of disease, with the fact that
abnormal methylation of tumour suppressor genes and oncogenes can cause
cancer. However, the role of epigenetics in disease doesn't stop there. It can
play a role in the development of many other dliseases, including Fragile-X
syndrome, Angelman syndrome and Prader-Willi syndrome.
Epigenetic changes are reversible, which makes them good targets for new drugs to combat diseases they cause. These drugs are designed
to counteract the epigenetic changes that cause the diseases.
For example, increased methylation is an epigenetic change that can lead to a gene being switched off. Drugs that stop DNA methyłation
can sometimes be used treat diseases caused in this way.
The drug azacitidine is used in chemotherapy for types of cancer that are caused by inereased methylation of tumour suppressor
genes. Tumour suppressor genes usualiy slow cell division, so if they are switched off by methylation, cells are able to divide uncontrollably and can form a tumour. Azacitidine inhibits the methylation of these genes by physically blocking the enzymes involved in the process.
Decreased acetylation of histones can also lead to genes being switched off. HDAC inhibitor drugs, e.g. romidepsin, can be used to treat
diseases that are caused in this way including some types of cancer. These drugs work by inhibiting the activity of histone acetylase
(HDAC) enzyme which are responsible about removing acetyl group from the histone without the activity of HDAC, the genes remain
acetylated & the protein they code for can be transcribed.
An experimental technique for correcting defective genes that are responsible
for disease development
The most common form of gene therapy involves inserting a normal gene to
replace an abnormal gene
Replacing a mutated gene that causes disease with a healthy copy of the
gene.
Inactivating, or “knocking out,” a mutated gene that is functioning improperly.
Introducing a new gene into the body to help fight a disease.
The concepts of Gene Therapy was introduced in 1960. Gene therapy involves how you altering the
defective genes (mutated alleles) inside cells to treat genetic disorders and cancer do this depends
on whether the disorder is caused by a mutated dominant allele or two mutated recessive alleles.
If it's caused by two mutated recessive alleles you can add a working dominant allele to make
up for them.
If it's caused by a mutated dominant allele you can 'silence' the dominant allele ( e.g. by sticking
a bit of DNA in the middle of the allele so it doesn't work any more).
Both of these processes involve inserting a DNA fragment into the person's original DNA just like in
recombinant DNA technology, you need a vector to get the DNA into the cell. A range of different
vectors can be used, eg, altered viruses, plasmids or liposomes ispheres made of lipid).
● A vector delivers the therapeutic gene into a patient’s target cell
● The target cells become infected with the viral vector
● The vector’s genetic material is inserted into the target cell
● Functional proteins are created from the therapeutic gene causing
the cell to return to a normal state
There are two types of gene therapy:-
1. Somatic therapy
This involves altering the alleles in body cells, particularly the cells that are mest affected by the disorder.
Example
Cystic fibrosis (CF) is a genetic disorder That's very damaging, to the respiratory system, so somatic therapy for CT targets
the epithelial cells fining the lungs.
Somatic therapy doesn't affect the individual's sex cells (sperms or eggs) though, so any offspring could still inherit the
disease.
2. Germ line therapy
This involves altering the alleles in the sex cells. This means that every cell of any offspring produced from these cells will
be affected by the gene therapy and they won't suffer from the disease, Germ line therapy in humans is currently illegal
though
There are also many ethical Issues associated with gene therapy.
Example
some people are worried that the technology could be used in ways
other than tor medical treatment, such as for treating the cosmetic
effects of aging, Other people worry that there's the potential to do
more harm than good by the technology e.g. risk of gene over
expression gene product is too much of missing protein
• Angiogenesis is the process which forms new blood vessels. Like
normal tissues in the body, tumors need to develop blood vessels
to supply oxygen and nutrients in order for them to grow and
spread. Angiogenesis inhibitors, which can be used to reduce or
slow down the spread and growth of some types of cancer by
suppressing the tumors ability to form new blood cells.
• https://youtu.be/Ep_nCSEDeAE
Angiogenesis can be a normal and healthy bodily process when new blood
vessels are needed. It occurs as part of growth in children, when the uterine
lining is shed each month in menstruating women, and when new blood
vessels are required in the process of wound healing. Researchers are actually
looking for ways to boost angiogenesis in the setting of tissue damage, such
as after a heart attack.
With cancer, this formation of new blood vessels (angiogenesis) is what
allows tumors to grow.
Intussusceptive angiogenesis
Sprouting angiogenesis
TYPE of angiogensis
Angiogenesis is of interest in cancer because cancers require
the formation of new blood vessels to grow and metastasize.
In order for cancers to grow to be larger than roughly one
millimeter (1 mm), angiogenesis needs to take place. Cancers
do this by secreting substances that stimulate angiogenesis,
and hence, the growth of cancer.
In addition to being a process needed for cancers to grow and
invade neighboring tissues, angiogenesis is necessary for
metastases to occur. In order for cancer cells to travel and set
up a new home somewhere beyond their origin, these cells
need to bring new blood vessels in to support their growth at
their new locations.
The process of angiogenesis involves several steps involving endothelial cells (the
cells that line the vessels). These include:
• Initiation: The process of angiogenesis must be activated by some signal (prior to
this, it's thought that the blood vessels must dilate and become more permeable)
• Sprouting and growth (proliferation)
• Migration
• Tube training
• Differentiation (maturation)
• We used the example of VEGF above, but there are actually dozens
of proteins that both activate and inhibit angiogenesis. While the
increased activity of activating factors is important, it's thought
that activation alone is not enough for angiogenesis to occur in
cancer. Factors that inhibit blood vessel growth also have to show
less activity than they otherwise would.
There are a number of different proteins that can stimulate (activate angiogenesis) through different signaling pathways.
1. Vascular endothelial growth factor (VEGF): VEGF is "expressed" in roughly 50% of cancers
2. Platelet derived growth factor (PDGF)
3. Basic fibroblast growth factor (bFGF)
4. Transforming growth factor
5. Tumor necrosis factor (TNF)
6. Epidermal growth factor
7. Hepatocyte growth factor
8. Granulocyte colony stimulating factor
9. Placental growth factor
10. Interleukin-8
11. Other substances including other cytokines, enzymes that break down blood vessels, and more
There are also a number of substances that play an inhibitory role to stop or prevent angiogenesis. Some of these include:
1. Angiostatin
2. Endostatin
3. Interferon
4. Platelet factor 4
5. Thrombospondin-1 protein (this protein appears to inhibit the growth
and migration of endothelial cells and activates enzymes that cause cell
death)
6. Prolactin
7. Interleukin-12
Thanks for your
attention
@tiu.edu.iq
