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EPIGENETICS AND CANCER
Revision paper: http://www
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com/nrg/journal/v18/n1/full/nrg
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Most of the genome is inaccessible, in that, only 1% of the genome is protein
encoding, which leaves 99% termed at first as ‘junk’ by the scientific field
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However, over the years, it was realised that this area plays quite an important part
and particularly, in epigenetics
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Epigenetics is defined as ‘above or in addition to genetics’, and this epigenomics is
the study of epigenetic modifications across as individual’s entire genome
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Epigenomics helps us understand:
- How a genotype gives rise to a phenotype
- How traits are inherited across generations of cells and organisms without
alterations in the DNA sequence
- How the structural adaptation of the genome facilitates gene activation or
repression
- Most epigenetic modifications are reversible!
o This diagram shows cell populations with different developmental potentials and
their respective epigenetic states
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o Whereby, coloured marbles correspond to different differentiation states – purple is
totipotent, blue is pluripotent, red is multipotent and green is unipotent
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o Therefore, the further down the marble rolls, the more developmentally restricted
the cell becomes
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Furthermore, epigenetics are inherited, and an example is the Calio Cat:
In cats, one of the several genes controlling fur
colour is located on the X chromosome, and
this gene has 2 alleles: orange fur is coded for
by the XB and the black fur is Xb
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Hence, in a patch of skin in which the B is
inactivated, that patch of fur will be black and
the patch of skin in which the X chromosome
carrying the b allele is inactivated, it will be
orange
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Other biological influences on the epigenome include:
- Cells can signal to their neighbours through direct contact
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Signalling
through direct contact is especially important during early embryonic
development, for example, during early nervous system formation
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o This kind of signalling is like tossing a ball
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Hormone signals ae released in one part of the body, then they travel through
the blood system to affect multiple cell types
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They are broadcast widely, and any cells
that are tuned in can pick them up
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Environmental factors also reach the epigenome through cell signalling
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o Some are indirect – stress triggers an array of signals that move from cell
to cell through the release of brain chemicals and hormones
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Furthermore, there is structural adaption of chromosomal regions, in order to
register, signal and perpetuate the altered activity state of DNA
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There exist proteins that can read, write or erase these structural changes
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The epigenome contains a combination of all chromatin modifications in any given
cell type
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For example, a activated area would contain these beads spaced out on the DNA,
whereas repressed would be signified by the these beads being clustered
together
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Chromatin is a complex of DNA and proteins that forms chromosomes within the
nucleus of eukaryotic cells
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Nuclear DNA does not appear in free linear strands; it is highly condensed and
wrapped around nuclear proteins in order to fit inside the nucleus
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One form of chromatin is called euchromatin, which is less condensed and can be
transcribed
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- Each histone octamer is composed of two copies, each of the histone proteins
H2A, H2B, H3 and H4
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- The chain of nucleosomes is then compacted further and forms a highly
organized complex of DNA and protein called a chromosome
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Furthermore, each of these histones (the beads) can be modified in a multitude of
ways on their N-terminals, termed tail, such as ubiquitination, methylation,
acetylation and phosphorylation – to name a few
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More than one-fifth of the amino acids in each of the core histones are either lysine
or arginine, and their positive charges neutralise the negatively charged DNA
backbone
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Importantly, histone modifications are not static, in that:
- Phosphorylation adds a negative charge
- Acetylation adds a positive charge
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- However, these modifications are dependent on each other due to the histone
crosstalk
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Decoding histone modifications – H3K9me3
- Histone H3
- Amino acid K at position 9
- Modification is a trimethylation
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These chromatin modifications affect DNA-dependent processes such as:
- Transcription
- Splicing
- Replication
- Repair
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- Euchromatin means that gene transcription is on, because the DNA is not tightly
packed
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DNA CpG Modifications:
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1% of the genome (CpG methylated
islands), whilst 1% is made up of hypo-methylated CG islands
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- Whereas, the latter consists of house-keeping genes, which means that they are
constantly transcribed, except due to loss of function mutations within these
loci
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These islands (both methylated and non-methylated) are not randomly distributed
in the genome and create variations between cell types because specific proteins are
attracted or repelled by modified forms of CG (cytosine and guanine)
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The CpG islands consist of over 500bp, of which 55% is CG content, that is associated
with promoters of 70% human protein encoding genes, and are hypo-methylated
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Of the total CpG content, 80% is found to be in repetitive sequences, such in
centromeres, telomeres, and are normally hyper-methylated – thus signifying an
inactive form and are silenced
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The meCpG writer, for example DNA MethylTransferase 1– DNMT1 functions to:
- Maintain methyltransferase
- Is involved in methylation of CpG sites in newly synthesized daughter DNA
strands to match the methylation pattern of the parental strand
- Directly binds to histone deacetylases to promote heterochromatin formation
and silence gene activity
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- MBD proteins also maintain silencing by maintaining methylation and histone
marks by being coupled with DNA
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The erasers are called the Tet-eleven-translocation protein family function to erase
methyl groups, such as 5-methylcytosine to cytosine
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CpG hypermethylation in promoters are associated with gene silencing, such as in
the tumour suppressor genes MLH1 (colon cancer), BRCA1 (breast cancer), PTEN
(brain and thyroid cancer), CDKN2A (p16Ink4a) (head, neck and lung cancers)
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- This is associated with genome instability and potential re-expression of
silenced repetitive elements
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However, these dysregulations mean that there are novel therapeutic targets, such
as the reversion of CpG methylation, particularly in myelo-dysplastic syndrome,
whereby methylation resulted in a massive reduction of RBCs
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- Such as decitabine and 5-azacytidine as demethylators
- HDAC inhibitors include: Vorinostat and Romidepsin
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Oncohistones, whereby a mutation in the histone itself causes DNA dysfunction
and an increase in genomic instability
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BET family of bromodomains, which are epigenetic reader proteins
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