What Does the Future Hold for the Study of Nucleic Acid Modifications in the Brain?

P.R. Marshall1, T.W. Bredy1'2

!The University of California Irvine, Irvine, CA, United States; 2The University of Queensland, Brisbane, QLD, Australia

Over the past 40 years, technological advances have made it possible to interrogate the entire genome; thus, the understanding of DNA modification has evolved significantly. Once considered to be a relatively static epigenetic mechanism, with its primary function restricted to the regulation of transcriptional programming during early cellular development, we now know that DNA methylation is a highly dynamic process in postmitotic neurons and plays a particularly important role in neuronal gene expression that directly impacts behavior. For example, in the adult brain, neuronal activity-induced changes in 5-methylcytosine (5mC) frequently occur outside gene promoters (Guo et al., 2011; Guo, Su, et al., 2011), and 5-hydroxymethylcytosine (5hmC) accounts for almost half of DNA methylation detected in the brain (Szulwach et al., 2011). Moreover, as is discussed herein, the base sequence can also dictate the relative probability that a region of the genome will be epigenetically modified. This relationship is important because it suggests that gene- epigenetic interactions should be considered in the context of a multilevel and bidirectional landscape, with other epigenetic regulators also acting to coordinate the function of the genome in a cell- and context-specific manner.

This correlation is particularly apparent in the discussions in Chapter 5 on non-CpG methylation and the functionally distinct role of 5hmC in the brain. However, despite this evidence much of the field still assumes that there is an inverse correlation between 5mC in gene promoters and gene expression. This leads us to ask what direction the field now needs to take. It is proposed that we will soon come to realize that it does not take millennia for DNA to change its function. Rather, mounting evidence suggests that DNA is constantly evolving and adapting in real time to its environment and that epigenetic modifications and related downstream effects on gene regulation rapidly contribute to phenotypic diversity from the level of cell function up to behavior. In the following sections, we present some of the most interesting molecular mechanisms related to genome regulation and how they are subject to DNA modification. It is evident that we have scratched only the tip of the iceberg with respect to this important mechanism of gene-environment interaction.

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DNA Modifications in the Brain ISBN 978-0-12-801596-4


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