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The new epigenetics

9 November 2009
By Professor Marilyn Monk
Emeritus Professor of Molecular Embryology at University College London's Institute of Child Health
Appeared in BioNews 533

All cells in the body have the same complement of 25000 genes, yet different cells in different specific tissues - such as nerve, muscle or gut - have different characteristics (phenotype). It follows that different subpopulations of genes within cells of differing function must be active or silenced depending on requirements for function in a particular tissue. Obviously, there will be genes concerned with metabolism, growth, and cell division - the so-called housekeeping genes - that will be active in all cells. Then there are tissue-specific genes that are only active in cells as required for function - neural genes only active in nerve cells, muscle genes only active in muscle cells, and so on - there are about 100 different cell types in the body. Only the tissue specific genes for one type of cell are active or expressed - the others are not needed and are silenced by epigenetic modification. Generally, the activation and silencing of subpopulations of genes determining tissue specific gene function in different tissues is laid down during development and is stably inherited cell to cell throughout life.

The science of epigenetics is concerned with this heritable cell to cell regulation of gene activity. The mechanism by which a gene is active or is silent depends on epigenetic modification superimposed on the gene. Broadly speaking, this can happen in three ways - methylation of the carbon ring of the cytosine base in the actual gene DNA, modification (acetylation, methylation or phosphorylation) of the amino terminal end of the histone tails in the nucleosomes (around which the DNA is coiled), or specific binding of small nuclear RNAs. These differing mechanisms associated with gene activation or silencing can act independently, or may be interdependent in that once one form of modification occurs to activate or silence a gene it will attract further modifications.

For several decades, interest in epigenetics has been largely confined to its role in orchestrating the regulation of gene expression in the formation of different organs and tissues in the shaping up of the embryo and fetus during development. Following on from this, the dynamic nature of epigenetic modification for certain inducible genes was demonstrated - the onset of gene expression may be dynamically associated with, for example, demethylation of the regulatory region (promoter) of the gene in the presence of its inducing stimulus.

Then, with the discovery of imprinting, the differential expression of paternally inherited and maternally inherited copies (alleles) of certain genes, it became clear that certain modifications influencing the potential of a gene to be expressed could pass through the germ line - through the egg or the sperm. This is a highly significant discovery as, until imprinting was demonstrated, a major objection to the possibility of Lamarckian inheritance (transgenerational inheritance of acquired characteristics) was the lack of a conceivable molecular mechanism. The passage of epigenetic modifications through the germ line means that the way we live our lives may influence the potential of the genes we pass to our offspring, and imbues upon us a certain longitudinal responsibility for future generations.

Now, in the last few years, several new and remarkable roles for epigenetics are appearing in the scientific literature. One is the conditioning of the newborn genome to its physical, nutritional and psychological environment, laid down as epigenetic regulation of gene expression in early childhood and affecting health and well being throughout life. Another is the highly dynamic role of epigenetic regulation of gene expression in the brain to regulate memory and behavioural conditioning, for example fear conditioning. And yet a third is the role of epigenetic regulation in the determination of many lifestyle diseases, particularly mental illness and cancer.

In these instances the epigenome may be seen as the interface between our genome (the genes we inherit) and the environment. The genome could be seen as the hardware and the epigenome (epigenetic programming of gene function) as the software. The old idea of Nature (genes) versus Nurture (environment) is outdated and now replaced by a more realistic view of a continual interplay between the environment (inner and outer) and our genes through epigenetic programming, thus monitoring and changing our interactions with our environment, again changing feedback to our genes, and so on. Our ever-changing epigenome constantly monitors our environment to determine who we are, our responses to external and internal stimuli, and the state of our health and well being.

Does Genetics Matter? Help - the annual conference of the charity that publishes BioNews, the Progress Educational Trust (PET), taking place on Wednesday 18 November at Clifford Chance in East London - will be an excellent opportunity to share ideas in this new epigenetic arena.

SOURCES & REFERENCES
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