Critical Thinking

How genes. DNA methyltransferases (DNMT’s) are the enzymes

How epigenetics contributes to the control of gene expression

 

Epigenetics is the study of heritable
(from one cell to another during cell division) changes in gene function that
do not involve changes in the DNA base sequence. Epigenetic modifications
concern nucleosome positioning, histone posttranslational modifications, DNA
methylation, and non-coding RNA’s.

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Epigenetic regulation is controlled by ‘writers’ which are enzymes that catalyse the introduction of
epigenetic marks, ‘erasers’ which are enzymes that remove
epigenetic marks, and ‘readers’ which are proteins that read the marks
and activate downstream cell signalling.

The presence of DNA methyltransferases
DNMT3A and DNMT3B which establish methylation and DNMT1 which maintains
methylation, allows control of gene expression at specific times in specific
tissues (particularly of developmental genes during embryonic development) and
helps maintain the correct epigenetic marking of the genes.

Although natural, if epigenetic
processes occur improperly, harmful behavioural and health effects can result.

DNA methylation

DNA methylation is the most well-known
epigenetic process, which occurs by the addition of a methyl (CH3) group to
DNA, influencing the gene function and expression. Two of the four DNA bases
can be methylated- cytosine and adenine, however the methylation of the 5th
carbon of the cytosine to form 5-methylcytosine (5-mC) is more widespread, with
adenine methylation receiving much less attention.

The methyl group projects into the
major groove of the DNA helix, directly preventing transcription binding, and
leads to changes in the chromatin structure that restricts access of
transcription factors to the gene promoter.

 

5-mC almost always occurs as paired symmetrical methylation
at a CpG site (where cytosine and guanine appear consecutively), resulting in
two methylated cytosine bases sitting diagonally to each other on opposing DNA
strands as seen in the left image.

 

Except for embryonic stem cells where
5-mC typically occurs in non-CpG sections, most CpG sites in genomic DNA are
heavily methylated, however areas with greater density of these CpG sites known
as CpG islands in germline tissues and near promoters of normal somatic cells
remain unmethylated, allowing gene expression to occur. Methylation of these
CpG islands in the promoter section of genes leads to turning off and
repression of the gene, however when these islands become hypermethylated, the
result can be transcriptional silencing of genes such as tumour suppressing
genes. DNA methyltransferases (DNMT’s) are the enzymes involved in the regulation of gene
expression such as the methylation of these tumour suppressor genes, and
therefore modulation of the activity of the DNMT’s (DNMT1, DNMT3A, DNMT3B) could be used to restore
hypermethylated tumour suppressor genes, and this has therapeutic potential
against diseases affected by hypermethylation such as cancer’s.

 

   Histone
modifications

Histones are proteins found in
eukaryotic cell nuclei which act to package DNA (through wrapping the DNA
around itself) into chromosomes. Histone modifications are known as
post-translational modifications (PTM’s), or marks, which can impact gene expression by altering
the chromatin structure and organising the genome into active sites of
euchromatin where the DNA is accessible to transcription factors or into
inactive types of chromatin known as heterochromatin where DNA is more compact
and less available to transcription.

Methods of histone modifications
include methylation, phosphorylation, acetylation, ubiquitylation, and
sumoylation. An effect of these processes is gene imprinting, where one of the
two alleles in a gene pair is silenced, which can be a problem if the expressed
gene is damaged or increases the organism’s vulnerability to potentially
harmful substances.

 

Histone acetylation occurs by the
addition of an acetyl (COCH3) group from acetyl CoA to the ?-amino group of lysine side chains, catalysed by histone acetyltransferases (HAT’s). This
neutralises lysine’s positive charge, weakening the interactions between
histones and DNA, thereby causing an increased accessibility for
transcriptional regulatory proteins.

This process is involved in the regulation of
cellular processes including chromatin dynamics and transcription, gene
silencing, and DNA replication. An imbalance of histone acetylation to
deacetylation is associated with tumorigenesis and cancer progression, and so
determining whether specific histones have been acetylated can help provide
information on acetylation patterns and sites, and this will also help improve
the understanding of epigenetic regulation of gene activation.

Histone methylation occurs when up to 3 methyl
groups are transferred from S-adenosyl-L-methionine to lysine’s or arginine’s
of histone proteins by histone methyltransferase (HMT’s).

Through chromatin-dependant transcriptional
repression/activation, HMT’s can control DNA methylation, and when this occurs
genes within the DNA bound around the histone can be activated or silenced.

 

Evidence of the effect of epigenetics in human populations

Several human studies
have shown that exposure to maternal stress during the prenatal period and
during labour, and stressful conditions during early childhood can be
associated with long-lasting health problems, with epigenetic regulation
thought to be involved.

It has been suggested
that deregulation of epigenetic pathways during the developmental stage results
in genome wide changes in gene expression in various bodily tissues including
the brain, affecting the functioning of neural circuitry, and has been linked
to psychiatric and physical disorders in later life.

Research showed that
exposure to a maternal depressed/anxious mood during the 3rd
trimester of gestational development, resulted in increased methylation of a
CpG rich region in the promoter of the Gr gene in the cord blood of new borns,
and these effects of methylation persisted beyond infancy. The levels of
methylation of this gene in the foetal cord blood were correlated to stress
response levels in infants, which suggested that a consequence of the
epigenetic variation was an impact on post-natal stress reactivity.

Further research into
maternal depression (and the increased cortisol levels associated) during
different stages of pregnancy, found that the dynamic changes in epigenetic
regulation of gene expression within the placenta had significant effects on
the child’s genome, for example through decreased levels of methylation in the
promoter of a gene that encodes the serotonin transporter.

The studies concluded
that changing patterns of methylation of placental genes can result in
environmental cues being passed onto the foetus potentially reprogramming the
foetus’s neurological function and affecting their response to certain
post-natal environments in later life.

In addition to
exposure to prenatal stress, further research also showed that a variety of
environmental factors surrounding the period of labour have been seen as
potential triggers of epigenome modulation, for example at around 3-5 days’
post birth, modulation patterns remained unchanged in infants born vaginally
but were decreased in those born by caesarean section.

Other events
surrounding birth such as maternal pyrexia, induction of labour using
artificial oxytocin or general anaesthetic were shown to cause long term health
effects such as type 1 diabetes, asthma, multiple sclerosis, and leukaemia.

Furthermore, studies
suggest early postnatal stressful experiences may also have an effect for long
term programming, whereby children who experienced unhealthy environments such
as parental neglect demonstrated differential patterns of DNA methylation,
particularly in genes that contribute to immune function and cell signalling
pathways including those involved in neural communication and brain
development, and subsequently these children tended to experience intellectual
impairment at a later age.

This diagram shows the scheme of
mechanisms linking exposure to early-life stress to later life health outcomes.

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