Investigating the role of DNA methylation in human growth disorders

In all our cells our genes which are made up of DNA control normal development into adulthood. The control of these genes affects how well a baby grows in the womb. If a baby is born very small, they can have brain damage and the knock on effects of this poor growth can often affect their health in later life. We have found that modifications called ?epigenetic? changes to the DNA on growth genes can result in poor growth in the womb. Using DNA samples from rare human syndromes with severe growth defects and normal DNA samples from small babies we will study these modifications to their DNA. To do this we will use new and sophisticated technology that can tell us exactly how these ?epigenetic? changes effect growth gene expression. Once we have identified these epigenetic marks we will be able to design biomarkers and diagnostic tests for treatment of the health problems associated with severe fetal growth problems.

Understanding the basis of inherited disease remains an important and substantial goal in human health research. Mutations in the DNA sequence account for inherited disease in the large part, but increasingly it is being recognised that epigenetic factors such as DNA methylation play an important role. Identifying and understanding the interplay between genetic and epigenetic mutations is important for elucidating disease mechanisms and for developing strategies to identify biomarkers, diagnostic tools and treatments. We present data showing that we can interrogate human DNA methylation genome-wide and we have used bioinformatic tools to confirm known regions of hypomethylation in patients with a well-characterised human growth disorder, Silver Russell Syndrome (SRS). We propose to mine high-resolution methylation data generated by next generation sequencing methods from SRS patients who lack known methylation defects for novel epimutations. Furthermore, we will examine the methylomes and exomes of a group of rare, extreme syndromic growth disorders and a group of common non-syndromic (interuterine growth retardation-IUGR) growth disorders for which the underlying aetiology is poorly understood. With this strategy we will identify novel epimutations and disease genes and characterise associations between methylation variation and genetic variation.