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Changes in the epigenome induced by the environment have been documented in diverse animal phyla, ranging from insects to rodents to humans. These include chromatin remodeling, histone tail modifications, and DNA methylation, and more recently the list has expanded to encompass noncoding RNA and microRNA gene regulation (Matzke and Birchler 2005). Thus, it is increasingly recognized that exposure to chemical, nutritional, behavioral, and physical factors alters gene expression and affects health and disease not only through mutation of but also through modification of the epigenome. Moreover, such exposures have been directly linked with subsequent disease formation through deregulation of epigenetic mechanisms. Unlike genetic mutations, these epigenetic changes are potentially reversible, providing a unique avenue to improve human health. Consequently research in epigenetics has increased dramatically in the last few years (Figure 1).    Figure 1  Literature search results show increasing interest, albeit at different growth rates, in both epigenomics (left axis) and repetitive elements (right axis) over time.    The term “epigenetics” was popularized in the early 1940s by developmental biologist Conrad Waddington (1940) to explain “the interactions of genes with their environment, which bring the phenotype into being.” In the 1970s, Holliday and Pugh (1975) first proposed covalent chemical DNA modifications, including methylation of cytosine-guanine (CpG) dinucleotides, as the molecular mechanism to explain Waddington's hypothesis. The revelations several decades later that X inactivation in mammals and genomic imprinting are regulated by complex and multifactorial mechanisms (Monk 1988; Willard et al. 1993) resulted in an updated definition, describing epigenetics as heritable changes in gene expression that occur without a change in DNA sequence, including the modification of DNA methylation and chromatin remodeling (Wolffe and Matzke 1999). The genomics revolution inspired the investigation of genome-wide rather than local gene analyses, and the term “epigenomics” was coined as the study of the “effects of chromatin structure including the higher order of chromatin folding and attachment to the nuclear matrix, packaging of DNA around nucleosomes, covalent modifications of histone tails (acetylation, methylation, phosphorylation, ubiquitination), and DNA methylation” (Murrell et al. 2005). Finally, evidence that demonstrated the resistance of certain gene loci to methylation reprogramming during embryogenesis revealed that epigenetic modifications can be inherited not only mitotically but also transgenerationally (Lane et al. 2003; Morgan et al. 1999; Rakyan et al. 2003).  DNA methylation is the most widely studied form of epigenetic modification and occurs within the one-carbon metabolism pathway, which is dependent upon several enzymes in the presence of micronutrient cofactors, including folate, choline, and betaine derived through the diet. In mammals, DNA methylation is primarily a stable repressive mark found at cytosines in CpG dinucleotides; however, its regulation is more dynamic than previously believed (Maunakea et al. 2010). For example, recent evidence for methylation of non-CpG cytosines in human embryonic stem cells suggests that methylation at non-CpG sites may be important to developmental homeostasis (Lister et al. 2011). It has been documented that CpG dinucleotides are greatly underrepresented in mammalian genomes because of spontaneous deamination of 5-methylcytosine to thymine and subsequent fixation in a population over evolutionary timescales (Holliday and Grigg 1993). Thus, the majority of unmethylated CpG sites occur within CpG islands, defined as discreet regions containing a preponderance of CpG content (Deaton and Bird 2011). The resulting uneven distribution of CpG islands is thought to result from uniform genomic CpG site deamination and conversion coupled with the regeneration of new CpG islands found in repetitive elements with expansion by retrotransposition (Xing et al. 2004). Normally, CpG islands are located within or near gene promoters or in the first exons of housekeeping genes. In contrast, the body and regulatory elements of repetitive DNA sequences, such as transposable elements, are methylated, consequently inhibiting the parasitic transposable and repetitive elements from replicating by transcription. Of important note, however, not all animals use DNA methylation as a gene repression mechanism; for example, the model organisms fruit fly (Drosophila melanogaster) and roundworm (Caenorhabditis elegans) lack appreciable DNA methylation, whereas other insects and nematodes do retain DNA methylation machinery (Gutierrez and Sommer 2004; Maleszka 2008).  Epigenetic manipulation of cellular phenotype is also driven by alteration of chromatin structure by covalent histone modifications and incorporation of histone variants into the nucleosome (Saha et al. 2006). Chromatin is a nucleoprotein complex that packages linear genomic DNA by means of an array of nucleosomes. Each nucleosome consists of about 147 base pairs of DNA coiled around an octamer of histone proteins. Each octamer contains two copies each of the four core histones, H2A, H2B, H3, and H4. Chromatin may be further modified by association with linker histones, histone variants, and nonhistone proteins as well as myriad posttranslational modifications of histone proteins, including histone acetylation, methylation, ubiquitination, phosphorylation, and ADP-ribosylation (Caiafa and Zampieri 2005; Cheung and Lau 2005). Histone acetylation is usually associated with transcriptional activation because the affinity of histone proteins for DNA is reduced and chromatin packaging is relaxed. Histone methylation results in various transcriptional consequences depending on histone number and the lysine residue modified (Kouzarides 2007). Each lysine residue may be methylated in the form of mono-, di-, or trimethylation, adding enormous complexity to the histone code (Jenuwein and Allis 2001).  Furthermore, histone modifications interact with DNA methylation patterns to recruit multi-subunit chromatin–protein complexes, adding yet another layer of complexity to epigenetic gene regulation. For example, in this issue, Kim and Kim (2012) examine protein complexes affecting epigenetic mark placement. Two histone marks in particular, H3K27 trimethylation and H3K9 trimethylation, are well-characterized repressive chromatin marks important in genic and nongenic regions of the metazoan genomes, but the mechanisms by which these marks are targeted are not wholly understood. Herein Kim and Kim provide evidence that in mammals H3K27 and H3K9 trimethylation mark distinct regions of the genome, whereas the repressive polycomb repressive complex 2 histone-modifying complex works in concert with DNA-binding proteins such as JARID2, AEBP2, and YY1 to target histone modifications. Specifically, deep sequencing approaches, including chromatin immunoprecipitation-seq sequencing, are employed to evaluate the genome-wide distribution of histone modification marks in mammals.

Introduction: The Use of Animals Models to Advance Epigenetic Science