Over the past several decades, recognition has grown within the scientific community that DNA encodes information in other forms than merely the nucleotide sequence. All four canonical DNA bases—adenosine, guanosine, thymidine, and cytosine—are known to occur in covalently modified forms within the genome, and nonstandard bases, such as inosine and uracil (Alseth, Dalhus, & Bjoras, 2014; Guo, Su, Zhong, Ming, & Song, 2011b; Hardisty et al., 2015), have also been identified. These modified bases can control the way the genome is packaged, accessed, and interpreted by cellular machinery, and they likely have essential roles in transcriptional regulation.

More than 90 years of research has contributed to our understanding of how and why these bases occur in the genome. In the last decade, the availability of affordable high-throughput sequencing and the advent of epigenomics workflows have vastly increased our capacity to interrogate these modifications at the genome-wide level. Emerging technologies are making it possible to study DNA modifications by using a low amount of input material, and exciting questions are now being asked about the role of modified DNA bases in very specific tissue types or even single cells.

Many enduring questions within neuroscience come back to the observation that the brain is able to respond to the environment and adapt and learn through a process of change, which is lifelong. The field of epigenomics represents an attempt to address this observation by considering the ways in which neurons might encode information without altering the underlying nucleotide sequence. In the next section, we address the application of epigenomic techniques in the context of neuroscience, to study covalent DNA modifications in the brain.

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