Originally published in The Australia Times Science Magazine, Vol.2 No.7 (July) 2014
Most
people are aware that deoxyribonucleic acid, or DNA, encodes the information
that controls the development and function of all living organisms. This information
is organised into regions called genes and the complement of DNA information
that exists in any organism is known as its genome.
In
complex multicellular organisms such as humans, the genome is a database of
master plans for the entire body. But more than a decade since the human genome
was decoded, several fundamental questions regarding genome regulation remain
largely unanswered.
What
controls the development of more than 200 distinct cell types from this single
source of genetic information? How are genes that serve special roles in the
pancreas or brain prevented from being ‘switched on’ in other organs? And why
does the activity of some important genes change in diseases such as cancer and
diabetes?
We
now know that these questions cannot be answered solely by understanding the
DNA code. The exciting field of epigenetics is at the frontier of research into
the essential processes that control genes and how these differ between cell
types under normal and disease conditions.
Genes: the master plans for life
At
the simplest level, genes provide instructions for the construction of
proteins.
Because
proteins are fundamental to a vast array of processes that govern life, reading
and correctly decoding the biological information written in genes is critical
to normal cell function. To do this, cells possess decoding hardware that turns
the information stored in genes into messenger transcript molecules composed of
ribonucleic acid (RNA). Proteins can then be constructed by using the
information in the RNA as a template.
The amount of any given protein is primarily controlled by the amount of RNA that can be made from the corresponding gene. In this way, genes can be viewed as the master plans for the construction of a building. RNA messenger transcripts are the intermediate copies of these plans that can be taken off site, while proteins are the final products or buildings. Although in other cases, the RNA molecules themselves can be the final product.
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DNA
(genes) codes for RNA molecules that are templates for protein synthesis. In some cases, the RNA is the final, functional product |
One genome, many cell types
Humans
and other animals are composed of many different cell types that form distinct
organs and tissues.
Despite this remarkable
variation, all cells within the body are derived by cell division from a single
origin - the fertilised egg - and therefore contain identical DNA . Each cell type requires
access to only a certain combination of master plans (gene program) to fulfil
their job.
For
example, expression of specific genes by immune cells causes them to look and
behave entirely differently to kidney, nerve, or red blood cells. The immune
cell accesses a gene program that encodes proteins required to defend the body
against infection, whereas nerve cells only access genes needed to be a nerve
cell.
Accessing
the wrong gene programs can cause severe developmental and biological
consequences. It is therefore critical that a cell activates (switches on) and maintains the correct gene programs while
simultaneously silencing (switching
off) unwanted genes.
But how do cells achieve this
selective process with the necessary precision? Numerous scientific studies
have shown that the physical shape and organisation of the DNA is central to the
control of gene expression.
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|
All
cells within the body contain identical DNA because they are derived
by cell
division from the fertilised egg
|
The complex organisation of DNA
Each cell contains around two meters of DNA that needs to be
compacted within a microscopic nucleus.
Unlike
a lot of popular descriptions, DNA does not exist in the cell as long,
free-floating strands. In fact DNA wraps around small proteins called histones
like thread on a spool, allowing it to be organised and packaged with
remarkable efficiency. This combination of DNA and histones (as well as other
small proteins) is called chromatin.
The
key to gene activation is the interaction between decoding hardware and the
DNA. Interruption of this process effectively silences the gene by preventing
RNA from being made. So when DNA is
loosely associated with histones, genes are accessible to the decoding hardware
and can therefore be ‘switched on’. On the other hand, genes are ‘switched off’
when the DNA is tightly wrapped around histones, mostly because they become
buried within the chromatin structure.
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| Chromatin conformation and DNA accessibility are central to gene expression |
Tagging the chromatin for gene expression
Only
recently have scientists begun to truly understand how chromatin transitions between
‘on’ and ‘off’ states.
Research
has found that small chemical tags can be attached to histone proteins or directly to the DNA itself. Importantly, addition or removal of these tags controls
how dense or loosely the DNA wraps around histones. This means they can also control
which genes are switched on or off by guiding when and where the decoding hardware
can perform its role.
Because
these chemical tags can regulate changes in gene expression independently of
the DNA sequence, they are called epi-genetic
(above or over the genome).
Collectively, epigenetic tags comprise the epigenome. While all cells within
the body effectively have the same genome, the epigenome determines the gene
program and therefore the cell type.
The
discovery and characterisation of a vast array of epigenetic modifications has
revolutionised the study of genetics, developmental biology, and human disease.
Unique patterns of epigenetic tags are established for each cell type early in
the process of differentiation from a fertilised egg. These epigenetic patterns
closely correspond to different gene programs and are stably maintained through
cell division.
However,
changes to epigenetic tags can have considerable consequences for a cell
because this alters the gene program. For example, abnormal gene silencing caused
by the distortion of epigenetic patterns has been linked with developmental
disorders as well as several types of cancer. Changes to the epigenome can also
accumulate with time and have been proposed to contribute to ageing.
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| Epigenetic changes can regulate transitions between on and off states of gene expression |
Epigenetics and human
disease
Recent
years have witnessed a rapid increase in the epigenetic analysis of human
diseases, with numerous studies
finding that the environment of the cell can greatly influence epigenetic
patterns and therefore gene regulation.
Factors
including smoking and nutrition have been shown to change the epigenetic tags
on genes that are associated with the development and progression of human diseases.
Prime
examples are the specific epigenetic changes linked with the abnormally high
blood sugar levels experienced by people with diabetes. Recent findings suggest
that these changes could drive some of the secondary effects of diabetes
including heart disease, blindness, and kidney failure. And the fact that some
epigenetic tags persist over the long term may explain why diabetic patients
can continue to develop secondary complications many years after they have controlled
their blood glucose.
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| A rapid increase in the number of epigenetic studies associated with human disease in the past 10 years. Source: NCBI PubMed search terms 'epigenetics' and 'human disease' |
The language of the genome
Two
main factors determine if a gene is switched on or off.
First the DNA encoding a gene
must be unwound from histone spools to allow the decoding hardware to gain
access. Second, the decoding hardware must turn the information stored in the
gene into RNA so the final protein product can be made. Patterns of epigenetic
tags sit on top of the genome and direct the activation or silencing of genes
by allowing the chromatin to unwind or condense. Different patterns regulate different
gene programs that give rise to many different cell types from the same genome.
The epigenome can be thought of as the grammar that provides context for the language of DNA. In the same way that grammatical errors can cause the intended message of a sentence to be lost, tight control of the epigenome is central to the way genetic information is expressed by cells. This control can be affected by environmental factors, altering gene programs that contribute to the development and progression of disease.
Many
researchers anticipate that understanding how specific genes are epigenetically
altered in diseases such as diabetes, heart disease, and cancer may provide new
avenues for more effective therapy.
While significant progress has
been made in recent years, the characterisation of epigenetic changes in human
diseases remains a formidable challenge for biologists.
References
1.
International Human Genome
Sequencing Consortium (2001). Initial sequencing and analysis of the human
genome. Nature 409 (6822): 860–921. PMID: 11237011
2. Venter D (2003). A Part of the Human Genome Sequence. Science 299(5610):1183–4. PMID: 12595674
3. Doenecke D (2014). Chromatin dynamics from S-phase to mitosis:
contributions of histone modifications. Cell
Tissue Research 356(3):467-75. PMID: 24816984
4. Chen QW et al (2014). Epigenetic regulation and cancer (review). Oncology Reports 31(2):523-32.
PMID: 24337819
5. El-Osta A et al (2008). Transient high glucose causes persistent epigenetic
changes and altered gene expression during subsequent normoglycemia. Journal of Experimental Medicine 205(10):2409-17 PMID: 18809715
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(2013). Epigenetic changes in diabetes. Clinical
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