AB021. Epigenetics and disease—lessons from imprinting disorders

Abstract: Different cells in the body are characterised by different functions and different levels of gene expression despite each sharing the same genetic code. This variation in gene activity from cell to cell is achieved by mechanisms and processes that are collectively termed epigenetics. These epigenetic changes alter gene expression without altering the DNA sequence. One epigenetic mechanism that is readily measured is DNA methylation. It is potentially reversible and heritable over rounds of cell division. Furthermore such epigenetic modification of DNA can be influenced by environment, gene interaction or by stochastic error and there is a higher rate of epimutation than DNA mutation. Variation in DNA methylation is a well-recognised cause of human disease and is likely to play a pivotal role in the cause of complex disorders. The challenge is to identify consistent epigenetic alterations of aetiological significance, given that epigenetic modification of DNA differs between tissues, occurs at different times of development within the same tissue and is sensitive to continual environmental factors. This makes it difficult to determine whether epigenetic mutations are a primary cause or secondary to the disease process. Genomic imprinting is one of the best understood examples of epigenetic regulation of gene expression. The expression patterns of imprinted genes are characterised by expression from only one allele (of the pair) in a consistent parent of origin manner. The pattern is set by targeted methylation within the male or female germ line that resists the post fertilisation waves of demethylation of the zygote. Imprinted genes are thought to play an important role in fetal growth and their carefully regulated expression is important for normal cellular metabolism and human behaviour. Several well-known disorders of imprinting are known including Beckwith Wiedemann syndrome, Transient Neonatal Diabetes, Temple syndrome, Wang Kagami Ogata syndrome, Russell Silver syndrome, Angelman syndrome Prader Willi syndrome and Pseudohypoparathyroidism type 1B. Only a proportion of people with these syndromes have a true epigenetic error, as uniparental disomy (inheritance of both chromosome homologues from one parent with no contribution from the other) and copy number variation are more common underlying causes. Studies to determine the cause of seemingly ‘true’ epigenetic aberrations, identified in imprinting disorders, may provide helpful insights into the causes of epigenetic mutations in general. For example the work on imprinting disorders has led to the identification of ZFP57, as a gene essential for DNA methylation maintenance.

Keywords: Epigenetic mutations; DNA methylation; imprinting disorders