It is over twenty years since epidemiological studies revealed that there was a relationship between patterns of early growth and risk of conditions such as type 2 diabetes in later life. Studies of identical twins, individuals who were in utero during periods of famine and animal models have provided strong evidence that the early environment, including early nutrition, plays an important role in mediating these relationships. The concept of early life programming is therefore widely accepted. However the mechanisms by which a phenomenon that occurs in early life can have long-term effects on the function of a cell and therefore metabolism of an organism many years later are only starting to emerge. Growing evidence suggests that epigenetic mechanisms (including DNA methylation, histone modifications and miRNAs) leading to changes in gene expression play an important role in developmental programming. Several transcription factors have been shown to be susceptible to programmed changes in gene expression through such mechanisms. These conceptually are attractive targets of programmed epigenetic regulation, as through regulation of their expression a network of other genes will be regulated. We have demonstrated that expression of HNF4 alpha, a key developmental transcription factor previously implicated in diabetes risk, was reduced in pancreatic islets following suboptimal nutrition in early life through programmed changes in DNA methylation and histone modifications. Our recent studies have also demonstrated that post-transcriptional regulation of gene expression through alterations in miRNA levels also play a key role in mediating the effects of early nutrition on cellular memory. We demonstrated that maternal protein restriction in rodents and low birth weight in humans led to a permanent increase in expression of miR483-3p and a reduction in its target GDF-3 in adipose tissue. Further understanding of the extent and nature of these programming mechanisms could enable the development of preventative and intervention strategies to combat the burden of diseases such as type 2 diabetes.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: Declaration of Funding: This work was supported by the BBSRC, MRC and British Heart Foundation.