Epigenetics in health and disease
Variations in traits that are not due to changes in DNA sequence are in the realm of epigenetics. At the heart of gene expression control, epigenetic changes include adding methyl groups to the DNA – i.e. DNA methylation. These modifications occur mainly at cytosine in the DNA backbone, the CpG site, to form 5-methylcytosine. The 'Genome-wide study of human epigenetic regulators' (EPIX) project has studied the proteins that can recognise methylated DNA and mediate the effects of DNA methylation, which could act as additional levels of control in gene expression and therefore regulating essential cell functions such as DNA repair and ultimately have an impact on disease development. Specifically, the researchers looked at the binding sites of methyl-CpG binding proteins (MBPs) in human cells. EPIX researchers investigated the action of three main groups of proteins in mammals that bind MBPs. Two proteins in particular, ZBTB4 and ZBTB38, were identified with key roles in cell functions. Targets, mode of action and, ultimately, biological function of these proteins were recorded to give insight into their importance in cell function control. Accumulation of one protein, ZBTB38, caused massive DNA replication and ultimately chromosomal instability. Another MBP plays an important role at the replication fork. In DNA repair, proteins were identified with roles in damage due to ultraviolet and oxidative stress. Development is a phase where gene expression control is crucial. The scientists looked at a specially generated mouse model. Absence of ZBTB4 caused an array of neurodevelopmental disorders such as anxiety in adult mice and other phenotypes, including smaller size and organs. The exact cause of these disorders is still under investigation. Expression of both ZBTB4 and ZBTB38 messenger RNAs is reduced in tumours from breast and prostate cancer respectively compared to healthy tissue. ZBTB4 regulates several genes involved in cellular transformation and invasion. The ZBTB38 level is related to prostate cancer stage, recurrence of cancer after surgery and response to chemotherapy. EPIX has generated substantial data on epigenetic changes and the molecular basis of diseases, in particular cancer. This provides a platform for further research into key proteins that may be used in diagnosis or development of therapeutic strategies.
Keywords
Epigenetics, disease, DNA methylation, genome, cancer
