Epigenetics
Introduction
The term "epigenetics" consists of two parts (epi = on top of) and genetics. Epigenetics therefore refers to the inheritance of characteristics, when cells divide and multiply, that are not the result of fixed changes in hereditary material.
It is easy to realise that this process must take place, since the many different types of body cells originate from a single fertilized egg cell. In the embryo totipotent stem cells differentiate into the various pluripotent cell lines that produce up to 200 cell types, including neurons, muscle cells, epithelium, blood vessels etc. While all these cells have an identical genetic makeup, they do behave very differently. Moreover, when dividing in the body, or when cultured, these differentiated cells will not loose their specific properties or change phenotype. Thus epigenetic changes are preserved when cells divide and multiply. Only under very special conditions, researchers have recently been able to revert the process. A handful of genes have been identified that can transform ordinary skin cells into induced pluripotent stem cells which look and act like embryonic stem cells.
Molecular aspects
What is the nature of the epigenetic changes that are responsible for the creation of a range of epigenomes? (cells with the same genetic makeup, but with different phenotypes) The molecular basis of epigenetic control of gne expression is complex. A starting point is the realization that in any given cell only a subset of genes will be actively used. Therefore all other genes must be switched off, while in another cell type, a different set of genes will be active. A number of principles have been discovered by which the function of genes can be influenced:
- physical access to genes can be modulated by the way the DNA molecule is wrapped around histone proteins to form chromatin and chromosomes superstructures.
- in mammals, gene promoter regions also need to be exposed to the transcription apparatus of the cell in order for the gene to be active. Usually DNA is methylated, resulting in a closed chromatin structure, but removal of methyl groups will expose the stretch of DNA and thus influence its activity.
- methylation of DNA also influences the functional integrity of the overall structure of chromosomes, therefore changes could influence the evolution of the underlying DNA information.
- - the cell may further control the transcription apparatus itself. RNA is the intermediary messenger molecule before proteins are produced from the DNA information. It is known that RNA molecules can be modified and that small RNA molecules can interfere with DNA transcription. Even the resulting proteins can be the subject to post translational modification.
- in mammals, gene promoter regions also need to be exposed to the transcription apparatus of the cell in order for the gene to be active. Usually DNA is methylated, resulting in a closed chromatin structure, but removal of methyl groups will expose the stretch of DNA and thus influence its activity.
- methylation of DNA also influences the functional integrity of the overall structure of chromosomes, therefore changes could influence the evolution of the underlying DNA information.
- - the cell may further control the transcription apparatus itself. RNA is the intermediary messenger molecule before proteins are produced from the DNA information. It is known that RNA molecules can be modified and that small RNA molecules can interfere with DNA transcription. Even the resulting proteins can be the subject to post translational modification.
The figure shows how DNA can be methylated, how it is wrapped around histones and organized in chromosomes.
While all these processes may lead to either activation or repression of certain genes, the basic DNA sequence remains unchanged. Epigenetic control of gene expression is thus fundamental to the process of cell differentiation.
We are more than the sum of our genes
Interesting results in human studies is carried out on identical twins who have identical DNA properties. Research revealed that, during their lifetime, the DNA in the twins is modified differently so it's not really true to say that they are still identical when they grow up. It is hypothesized that this may explain the fact that sometimes only one of the twins develops a disease with genetic components, like diabetes, while the other does not. Dissimilar epigenetic changes in the two individuals, as caused by environmental factors (eating habits, stress, chemicals), may provide explanations. Epigenetic regulation is therefore one way to explain the rapid increase in incidence of diabetes and could be a central mechanism by which environmental factors influence development of diseases.
Epigenetic inheritance
The foregoing described epigenetic changes only occur once, when individuals grow up and their body cells differentiate. However, some epigenetic changes, termed epimutations, have also been shown to be transmitted from one generation to the next. Epimutations are thus inherited changes in gene expression that are not due to changes in the actual base pair sequence of DNA.
The epigenetic inheritance of altered phenotypes is a surprising finding. It goes against the idea that inheritance is only driven by the DNA sequence as the only component that carries information with respect to the offspring's ultimate phenotype. The occurrence and inheritance of epimutations are likely to have rules completely different from those of Mendelian genetics. The inheritance of epigenetic phenotypes was first reported in plants but is now also shown in other organisms, including microorganisms, fruit flies and mammals.
Advances in epigenetic research hold the promise to yield novel insights for gene regulation, cell differentiation, stem cell plasticity, developmental biology, human diseases, infertility and aging. A central emerging concept is emerging that there is an 'epigenetic code', which considerably extends the information potential of the genetic code.
