Download talk given by Brian Powling on 20 th January 2017

Notes on Epigenetics 2: talk given by Brian Powling on 20th January 2017
Brian started by reprising the talk he gave on Epigenetics in November 2015, which was just as well
for me, a poor ex-physicist with very little memory. I could just about remember that Epigenetics was
something to do with DNA not being the whole story of how we are made. It’s an extremely
complicated subject which Brian did his best to simplify. He’d based his talk on the book “The
Epigenetic Revolution’ by Nessa Carey and after trying unsuccessfully to make sense of the profuse
notes I took at the time, I finally gave up and bought the e-version of the book. As Brian had indicated,
it’s a very good book which is written in an accessible and often quite humorous style and details the
history of the research that has led to this developing subject but I still found the whole subject very
difficult to follow and only managed to read about half of the book before giving up completely. There
are so many acronyms and unfamiliar terms. Even with an e-book where you can easily find all
instances of a word, I was toiling. So, with all these caveats, here is my write-up of the talk, in the light
of the further reading. At the end, I’ve included a glossary of terms I struggled with.
Since our DNA doesn’t change throughout our lifetime
1. Why can’t childhood malnutrition be compensated for in later life?
2. Since monozygotic twins have identical DNA why is the concordance between them for
genetically-determined diseases not 100%?
3. Why does abuse or neglect in childhood increase the risk of mental health problems as an
adult?
The reasons are all epigenetic. The genetic code alone is not enough to explain what is going on.
Epigenetics can be defined as the set of modifications to our genetic material that change the way
genes are switched on or off but which don’t alter the genes themselves.
The entire sequence of our individual genetic material, including the DNA is called the genome. Genes
within the genome can be switched off. The DNA itself doesn’t change. It’s still there underneath.
One way in which this can happen is by methylation of the gene. The methyl group –CH3 is only able
to attach to the C component. The methyl attachment is reproduced when the DNA replicates.
Methylation causes a fairly permanent shutting down of the gene involved. Less permanent changes
in gene expression can be induced by acetylation of histones. Histones are particular proteins in cells
and some of them are found as little balls of protein that act like reels to wind up the very long DNA
molecule in the cell nucleus. If an acetyl group attaches to the histone it can cause changes to gene
expression in a sort of ‘try-it-and-see-what-happens’ way.
When the sperm and egg come together and fuse to start to make a new human being, that initial cell
is called a zygote. That single cell divides and starts a chain of division that ultimately produces a
recognisable human so each division is not the same as there are many different types of cell in the
body. The ‘Waddington landscape’ is an attempt to visualise the difference in potential of each cell
division. A zygote is at the top of a slope with the potential to make hundreds of different types of
cells. Further down the slope (i.e. after many divisions) branching points appear like little valleys at
various distances down the slope - see
https://www.researchgate.net/figure/262383220_fig2_Waddington's-classic-model-of-anepigenetic-landscape-11-A-developmentally-immature
Brian introduced the analogy of Waddington’s Tree rather than a landscape because he thought it
would be easier to visualise what was going on. As cells become more differentiated, they progress
from being in the trunk as stem cells, to the branch and then the twig with the fully differentiated cells
being the leaves.
So somehow cells can use genetic material in different ways to create all the different sorts of cells
required. Once a cell starts to become specialised (or differentiated in the lingo), it is very hard to
change it over to doing something different which is just as well or otherwise we’d have teeth growing
out of the skin of our arm or some else equally inappropriate. It’s easier to push it back up the slope
and start all over again.
It’s the chemical environment that the cell finds itself in that changes which genes are expressed or
promoted. It’s very difficult in the laboratory to get the environment right for every single cell division
which is thought to be one reason why cloned animals often have health problems like Dolly the Sheep
and arthritis.
When there is methylation of the DNA of a cell line still in development, the cells can be permanently
changed because the methylation is preserved when the cells divide. Sometimes this is obvious at the
time – e.g. the slight build of Audrey Hepburn due to starvation as a child, which never reversed.
Sometimes, a young person may appear unharmed, like those who have been abused as children, but
the chances of them developing mental health problems in later life is increased.
Histone modification can explain the differences between monozygotic twins. These twins tend to
get less like each other as they get older, particularly if they have lived apart. This fits with the known
fact that the histone structure becomes more complex as we get older. This reflects environmental
differences.
Gene therapy has struggled to deliver benefits in all sort of diseases. Epigenetic drugs may prove more
effective. They are now being approved by the FDA which will give this line of research a great boost.
Brian described the very large number of different epigenetic modifications to histone proteins and
the complexity of all the amino acids involved as ‘wondrous’. I agree.
M. Rose
Glossary
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Acetyl group CH3COAmino acid - a simple compound containing both a carboxyl (—COOH) and an amino (—NH2)
group
Chromosome – made up of protein and a single molecule of DNA. Humans have 23 pairs of
chromosomes.
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DNA – deoxyribonucleic acid – the double spiral molecule which replicates itself every time a
cell divides to form a daughter cell. It consists of six billion base-pairs where a base can be C
= Cytosine, G = Guanine, T=Thymine or A = Adenine. C can only pair up with G and T with A.
Gene – DNA can be thought of as split into many functional units called genes. Only 2% of our
DNA codes for proteins. The other 98% used to be thought of as ‘junk’ DNA but in the last 10
years, it has been recognised as being essential to epigenetic processes.
Genome – entire sequence of our individual genetic material, including the DNA.
Histone – molecular reel made of proteins that wraps up DNA in the cell. Acetylation of the
amino acid lysine in the histone causes changes in gene expression.
Methyl group –
CH3Protein – large molecule made up of chains of amino acids. Proteins are essential to life.
Stem cells – undifferentiated cells that can go on to produce more and more differentiated
cells