(2008) and Sweatt et al. (2013). It is worth

noting that all of these modifications I will describe have the basic biochemical characteristics of both regulating gene function (transcription) without altering the DNA sequence directly and of being (at least theoretically) capable of self-regeneration and self-perpetuation—in other words, of having the capacity to trigger a persisting change in gene function, even in the face of subsequent cell division or even organismal procreation. The biochemical capacity of a specific chemical reaction to trigger self-perpetuation UMI-77 supplier is the defining characteristic of a process involved in cellular information storage, as was initially commented upon in the neuroscience context by Francis Crick and John Lisman almost 30 years ago (Crick, 1984 and Lisman, 1985). Epigenetic mechanisms also possess this defining characteristic (Holliday, 1999). Covalent chemical modification of DNA, specifically cytosine 5′-methylation, has been referred to as the prima donna of epigenetics because it is an extremely powerful regulator of gene transcription (Santos et al., 2005). As a first approximation, DNA methylation is the proximal molecular mechanism that triggers,

and perpetuates over the full lifespan, the complete gene silencing in cells that is part and parcel PLK inhibitor of cell fate determination and perpetuation (Bird, 2002). DNA cytosine methylation is a core mechanism for silencing all the nonneuronal genes in all the cells in the body that are not neurons, for example. DNA cytosine methylation is the core driver of the epigenesis mechanism that Waddington Linifanib (ABT-869) postulated to exist (Holliday, 2006). In the existing literature, DNA cytosine methylation is described as occurring preferentially at cytosine-guanine dinucleotide sequences in DNA (so-called CpG sites) and is said to lead to attenuation of gene transcription. These generalizations are largely true, but based on recent discoveries it is clear that cytosine methylation also occurs at non-CpG sites and

that cytosine methylation can also be associated with transcriptional activation. This is the ambiguous nature of newly emerging fields. Besides DNA cytosine methylation, other chemical modifications of cytosine in DNA have also been documented to exist, including 5-hydroxymethylcytosine (hmC) formation and methylcytosine oxidation to generate 5-formylcytosine and 5-carboxylcytosine. The functional role(s) of these novel modifications are not fully established, and this is a hot area of investigation in the field at present. A central dogma of the epigenetics field has been that once DNA methylation patterns are established upon the genome in terminally differentiated cells, those modifications are permanent and essentially immutable.