Transgenerational Epigenetics

The regulation of gene expression through epigenetic modifications provides a dynamic route through which environmental experiences can lead to persistent changes in cellular phenotype. This plasticity plays an important role in mediating cellular differentiation and the potential stability of these modifications can lead to persistent and heritable variations in gene expression. Environmentally-induced changes in DNA methylation, posttranslational histone modifications, and expression of small noncoding RNAs have been observed following a broad range of environmental exposures. The process of DNA methylation whereby cytosine is converted to 5-methylcytosine is mediated by methyltransferases which either promote maintenance (i.e., DNA methyltransferase 1, DNMT1) or de novo DNA methylation (i.e. DNA methyltransferase 3, DNMT3) [1]. The process of methylation is dependent on the presence of methyl donors (provided by nutrients such as folic acid, methionine, and choline [2,3]) and the transcriptional repression associated with DNA methylation is sustained through methyl-binding proteins such as methyl CpG binding protein 2 (MeCP2, [4]). Histone proteins, which form the core of the nucleosome, also significantly alter gene expression through interactions with DNA [5]. Histones can undergo multiple posttranslational modifications, including methylation (diand tri-), acetylation, and ubiquitination, which can alter the accessibility of DNA and chromatin density. The prediction of transcriptional activation versus suppression in response to histone modifications is dependent on the type and location of modification [6]. For example, tri-methylation (me3) of histone 3 (H3) at the lysine 4 (K4) position within the histone tail is associated with transcriptional activation whereas H3K27me3 is associated with both increased and decreased transcriptional activity [7,8]. Small noncoding RNAs (RNA molecules approximately 20–30 base pairs in length that do not encode for a protein, for example, microRNAs, piRNAs), play a critical role in gene regulation through inhibition of translation and interplay with DNA methylation and chromatin [9]. Importantly, there is cross-talk between these epigenetic mechanisms that contributes to dynamic yet potentially stable levels of transcriptional activity [10,11]. It has become increasingly evident that experiences across the lifespan can induce modifications to the epigenome. Moreover, these epigenetic effects can have O U T L I N E