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Home arrow Health arrow DNA Modifications in the Brain. Neuroepigenetic Regulation of Gene Expression


One main obstacle for DNA epigenetic studies in addiction is how to integrate the various methodologies used (eg, Bock et al., 2010). In contrast to relatively standard ChIP- seq methods for other histone modifications, numerous approaches have been used to measure DNA epigenetic modifications. And with novel forms of DNA modifications discovered in the past few years (eg, 5hmC, 5fC, and 5caC), it would not be surprising to see still additional approaches being introduced (Booth et al., 2012; Song et al., 2013; Wu, Wu, Shen, & Zhang, 2014;Yu et al., 2012). Each currently used approach has its own pros and cons, which makes the choice of the right methodology particularly difficult.

For example, experimenters have to decide between cost and coverage, coding regions and intergenic regions, base resolution and fragmented resolution, quantitative and relative, small amount and large amount of starting DNA, and so on. Given the high cost and demanding bioinformatic support in whole-methylome analyses, initial studies largely depended on candidate gene approaches based on restriction enzyme cutting, antibody pulldown, or sodium bisulfite conversion. The inherent limitations of these approaches presumably explain why only relatively few genes were initially recognized to undergo methylation alterations in addiction models. The major imperative today, therefore, is to use next-generation sequencing technology with whole-genome coverage at single-base resolution, distinguishing between different cytosine modifications. This approach will become more feasible as sequencing costs decline. In the meantime, it is essential to cross-compare datasets derived not only from different brain regions, peripheral tissues, and addiction paradigms but also derived from various bionformatic platforms (Maze et al., 2014). Similarly, an important goal is to relate DNA methylomes to variations in DNA sequence data as they relate to vulnerability to drug addiction (H. Zhang et al., 2014).

As DNA epigenetic changes are identified, it will become crucial to manipulate these epigenetic states at selective loci to obtain causal insight into their role in gene regulation. A study from our group, using engineered zinc finger proteins or transcription activator-like effectors to target single types of histone modifications to single genes within a single brain region of interest in vivo, provides a means of obtaining such causal data (Heller et al., 2014). The increasing availability of genome-editing tools Tuesta & Zhang, 2014) offers additional technical approaches to achieve this important goal.

Another pressing question facing the field is whether DNA modifications, or any epigenetic modifications more broadly defined, are specific to a given drug of abuse or specific brain region. The existing literature, although still limited, suggests some common actions as well as many distinct actions. For example, one study demonstrated that DNA methylation at selected genes in VTA is required for the formation of reward- related memories, effects not seen for the NAc (Day et al., 2013).

We have been using the term epigenetics to refer to any chromatin modification that controls genomic function. However, the term is also used to describe heritable changes that occur without alterations of the underlying DNA sequence. Studies suggest that this heritable form of epigenetic regulation may also be involved in addiction. Several studies have shown that exposure of male rodent to drugs of abuse, or to stress, triggers behavioral changes in offspring (eg, Bale, 2015; Dietz et al., 2011; Gapp et al., 2014; Szutorisz et al., 2014). For example, prior cocaine self-administration by fathers can affect their offspring’s cocaine acquisition behavior (Vassoler, White, Schmidt, Sadri-Vakili, & Pierce, 2013). DNA methylation has been implicated in such inheritance of behavioral experience: sperm DNA from F0 males exposed to odor fear conditioning and F1 naive offspring revealed CpG hypomethylation of the Olfr151 gene, which was associated with increased behavioral sensitivity (Dias & Ressler, 2014). In addition, in vitro fertilization, F2 inheritance, and cross-fostering revealed that these transgenerational effects are inherited via parental gametes. Whether drugs of abuse can also affect transgenerational responses through DNA epigenetic modifications remains unknown. One study that probed this question has indeed demonstrated dynamic DNA methylation by reduced representation bisulfite sequencing DNA methylation profiling. The authors compared the NAc methy- lome in animals with and without parental cannabinoid exposure (Watson et al., 2015) and identified 1027 differentially methylated regions in the NAc of F1 adults associated with parental cannabinoid exposure. Many of the regions were related to genes involved in glutamatergic synaptic regulation. The goal of future studies is to provide causal evidence and precise molecular mechanisms by which such regulation occurs.

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