Before I start, I’d like to briefly
introduce myself and say hello. My name
is Jill Faircloth and I studied the PPS course in 2009-10 and then went on to
take the TSMB course the year after. I
posted a proper introduction
of myself in my first blog in March this year. I also gave some tips from previous years on managing the
revision and project work during the summer and thoughts on the two follow on courses.
Since that time I have started writing for The Brain Tumour Charity. The challenge there is to write explanations
of the highly technical research being sponsored in language that can be
understood by a non-scientist. This PPS
blog is a fantastic opportunity for me to continue to explore protein structure
research, which I enjoyed very much during my MSc, and hopefully to bring interesting
and relevant pieces of work to your attention.
Since you have only just begun to look at protein structure, however, I
thought I’d begin with a beginners guide to a hot topic: epigenetics.
The nature versus nurture argument has long been
a fertile source of entertaining and/or heated debate. As team nature pinned their colours to the
mast of the all powerful genome, the nurture camp would gleefully point out
that identical twins often exhibit different personalities, proof that the
genome is not the ultimate dictator. A
compromise was generally agreed upon whereby an individual’s personal traits
were thought to be formed by a nurture overlay on a nature foundation.
Epigenetics is the emergent science which
is poised to provide a more sophisticated answer both to the origins of
individuality and to the question of how dividing cells in a developing foetus have
the ability and apparent programming to become brain cells or liver cells or
any of the other very many different types of cells in a mature organism.
To understand the epigenome, we must first
look at the storage of DNA in the nucleus.
The familiar double helix of DNA is tightly wound around histone
proteins, packaged in groups of eight. Each
histone package is wound twice round by the helix to form a nucleosome so that
the DNA appears as a string sporting nucleosome beads along its length. This thread of nucleosomes is woven into a
rope called chromatin which, in turn, is woven into a chromosome.
Each of the diverse cells of the body
carries the same DNA which encodes the entire genome, that is, the code for
every protein required throughout the organism.
The epigenome is the system of molecules which acts upon the packaged
DNA to determine which of the genes encoded is activated in any particular
cell.
There are two key methods employed by the
epigenome, both of which can act to “turn off” particular genes:
- · the histone proteins can be post-translationally modified so that they bind the DNA more tightly, thereby shielding some genes from transcription, and
- · small chemical groups, predominantly the methyl group, bind to the DNA at CG pairs. A gene with several methyl caps will be blocked from transcription but removal of the caps will allow re-activation of the gene.
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Illustration
of epigenetic mechanisms adapted from Wikipedia
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Using this mechanism, cells with exactly
the same genome can behave differently since they can have different
combinations of histone modifications and methyl groups, i.e. different
epigenomes, controlling which genes are expressed and which are dormant. The processes which govern how cells acquire
these different epigenomes are not well understood although it is known that
the basic patterns are encoded on the genome and are then altered by
environmental factors. These include
signals from neighbouring cells so that a cell’s location is a key factor in
determining its unique epigenome.
Cell location is not the only factor,
however, as demonstrated in a study by Frago et al, (2005), which showed that although identical twins
begin life with the same epigenome, wide differences accumulate over time in
the acetylation of their histones and the methylation of different genes. This is thought to account for the clear
differences seen in the personalities and disease susceptibilities of monozygotic twins.
Another illustration of an environmental
factor is provided by some intriguing research into the epigenome of honey
bees. This study, (Lyko,
F. et al, (2010)), found that all
of the honey bees in a swarm have the same genome but as larvae they are given
a different diet, with future queens receiving royal jelly, and this creates a
difference in the methylation of more than 550 genes, including those for
histones.
Another study not only demonstrates that
diet has a strong epigenetic effect but also shows that this can have
transgenerational ramifications. Kaati et al, (2002) surveyed the long term
health of the residents of a sparsely populated region of Sweden called Ӧverkalix, which has been prone to cycles of high harvest yields
followed by years of famine. The results
showed that the paternal (but not maternal) grandsons of men who experienced
famine in preadolescence were less likely to die of cardiovascular disease
whilst paternal grandsons of men who enjoyed plentiful food were more likely to
die of diabetes. Interestingly, the opposite effect was found with women. Women whose paternal (but not maternal) grandmothers
were exposed to famine whilst in the womb, i.e. when their eggs were forming,
were found on average to have a shorter lifespan.
Epigenetic changes are usually considered
to apply to the genome within the lifetime of the organism but the Ӧverkalix study demonstrated that changes occurring in a sperm or egg
which is then fertilized can have a transgenerational effect. In other words, environmental effects on the
epigenome are potential evolutionary drivers.
Epigenetics also excites a great deal of
interest from a clinical point of view. A
great many cancers are found to be associated with both aberrant DNA
methylation patterns and a histone deviant called H2AZ. These abnormalities cause disactivation of
certain genes which could provide vital clues to the mechanisms of malignancies
and their possible treatment.
The National Institute of Health in the USA
allocated $190m to epigenetics research between 2008 and 2013, recognizing its
potential to explain the molecular processes behind human development and many
important human diseases. This
investment is bearing fruit with a recent announcement that variations
associated with several common diseases have been found in non-coding regions
of DNA. 88% of these regions are
responsible for regulating genes during foetal development and are known to be
susceptible to environmental exposures.
In other words, environmental factors experienced in utero produce
epigenetic changes which can manifest decades later as adult onset diseases (Maurano, M.T. et al, (2012)).
There is still much to discover in this
advancing field but between the potential for a whole new regime of therapies
and the possibility of an explanation of the interaction between nature and
nurture there is also much to be excited about.
