Developmental Epigenetics: Phenotype and the Flexible Epigenome

The term epigenetics has been widely used and abused (Greally, 2018) but the most compelling definition of epigenetics is the study of changes in gene function that are heritable through cell division, yet reversible, and that do not involve changes in DNA sequence - with heritability and reversibility being the key factors. Epigenetic information persists after the original inductive process that drove the modification has ceased, providing a cellular memory of the process or exposure in subsequent generations. Epigenetic marks allow the cell to remember what kind of cell it is irrespective of positional information and other extracellular information. Parent cells use epigenetic marks to tell their daughter cells what type of cell they will become, a message that may persist through thousands of cell divisions for the lifetime of the organism, unless they are actively erased or lost through epimutation. Epigenetic processes are fundamentally important for cell identity, lineage determination, regeneration and re-establishing of the next generation. They explain how an identical set of genomic instructions can generate all the required cell types for the organism without the need, in most cases, to alter gene sequence. The heritability through mitosis of the epigenetic information is relatively well characterized and acknowledged by the scientific community. Studies in various organisms, including plants and nematodes, have also revealed that epigenetic traits can be propagated through meiosis i.e., from one generation to the next. There is, however, much debate as to whether this holds true in mammals. The reason behind this questioning is the extensive epigenetic reprogramming that occurs twice in mammalian life, namely during the formation of the gametes and, after their fusion, in the embryo to be implanted. These events lead to an a priori complete (and this is where part of the debate stands) erasure of the epigenetic information that has been acquired during the parent's life, so that the new generation starts with a dean slate. In addition, it is difficult to confidently assign the heritability of a given molecular character that is acquired following exposure to stress or stimuli, solely to epigenetic information rather than a subtle and perhaps hard to track change in the underlying genetic material. From a molecular view, classic epigenetic marks include DNA methylation and the modification of proteins that lie on or over the DNA sequence itself (Cedar and Bergman, 2009). Chromatin and epigenetic are not, however, interchangeable terms. Chromatin-based mechanisms of gene regulation are not necessarily epigenetic, at least not more than classical regulatory processes involving transcription factors. It is, again, a matter of heritability of a status in the absence of the original trigger. Epigenetics can also involve non-coding RNA molecules, small and long, providing they are passed from one cell to another or from one generation to the next to maintain phenotype (Chen et al., 2016). There is, for example, limited argument to consider microRNAs, which control mRNA (and other types of RNA) stability and translation, as epigenetic regulators. Developmental epigenetics is not the study of these inherited factors per se, nor their global distribution across the genome, but is the study of the function of epigenetic processes during development, studies which may include the developmental programming of fetal growth trajectories and adult phenotypes.