Early Life Nutrition and Lifelong Health - Derbyshire Local Medical ...

BMA Board of ScienceEpigenetic inheritance is defined as biological processes that regulate mitotically or meioticallyheritable changes in gene expression without altering the DNA sequence. 284 Of particular relevanceis methylation of specific CpG dinucleotides in gene promoters and alterations in DNA packagingin nucleosomes arising from chemical modifications of the chromatin histone core around whichDNA wraps. The histone modifications include acetylation, methylation, ubiquitination, andphosphorylation. Other changes may involve other DNA associated proteins. Recently microRNAswhich affect DNA transcription and mRNA stability and translation into proteins have beenimplicated as a further mechanism for inherited epigenetic effects, 285 including those transmittedvia the paternal line.Epigenetic mechanisms are widely implicated in cancer. 286 In this situation the changes can bemodified by alteration of methyl group metabolism. 287 This suggests a mechanism by which folateand methyl donor status during development may operate. 288 Gene promoter methylation isimportant for asymmetrical silencing of imprinted genes 289 and retrotransposons. 290, 291 They alsoplay a critical role in a range of developmental processes. With the exception of imprinted genes,widespread removal of epigenetic marks occurs following fertilisation when maternal and paternalgenomes undergo extensive demethylation to ensure pluripotency of the developing embryoniccells. This is followed by de novo methylation just prior to implantation. 292, 293 About 70 per cent ofCpGs are methylated, mainly in repressive heterochromatin regions and in repetitive sequencessuch as retrotransposable elements. 294 DNA methylation also plays a key role in cell differentiationby silencing the expression of specific genes during the development and differentiation ofindividual tissues. For some genes there also appear to be gradations of promoter demethylationassociated with developmental changes in the role of the gene product. Changes in methylationwhich are associated with cell differentiation and functional changes are established at differenttimes during development of the embryo. The pattern of DNA methylation is copied during mitosisby DNA methyltransferase (Dnmt) -1 activity. This provides an ‘epigenetic memory’ of patterns ofgene regulation and hence cell function, which are established during development and which arepassed to the adult. 292 Environmental challenges at different times during development may inducestable changes in cell function, which persist in the adult organism. They may produce differentphenotypic outcomes and in humans differential risk of disease.Early life nutrition and lifelong health 67