Epigenetic marking of the BDNF gene by early-life adverse experiences

Abstract

Studies over the past half-century have made it clear that environmental influences in development, particularly stress and traumatic experiences, can remain pervasive across the lifespan. Though it has been hypothesized for some time that the long-term consequences of early-life adversity represent epigenetic influences, it has not been until recently that studies have begun to provide empirical support of experience-driven epigenetic modifications to the genome. Here we focus on this theme, and review current knowledge pertaining to the epigenetics of behavioral development. At the center of our discussion is the brain-derived neurotrophic factor (BDNF) gene, as abnormal BDNF gene activity is a leading etiological hypothesis by which early-life adverse experiences persistently modify brain and behavioral plasticity.

Figure 1

Epigenetic marking of the BDNF gene by early-life adverse experiences. Top panel – Schematic describing the organization of the rodent BDNF gene, which contains nine non-coding exons and a common coding exon (Aid, et al., 2007; Timmusk, et al., 1993). Asterisks designate promoters, tan boxes represent untranslated regions, and purple boxes represent protein coding regions. Bottom panels – Sequencing analysis in the prefrontal cortex of adults that had experienced favorable social interactions and environmental conditions during infancy revealed little or no cytosine methylation across 12 CG dinucleotide sites examined for BDNF exon IV (sites are numbered and in bold). Conversely, sequencing analysis of adult animals that had been maltreated as infants revealed significant cytosine methylation across the targeted region. Data recreated from Roth, et al., 2009.

Figure 2

Chromatin remodeling and its proposed role in governing the neurobiological consequences of early-life adverse experiences. Recent evidence indicates that adverse social interactions and stressful experiences early in development epigenetically mark genes in the CNS. Documented epigenetic changes include experience-driven DNA demethylation of the arginine vasopressin (AVP) and corticotropin-releasing factor (CRF) genes, and DNA methylation of the brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor (GR) genes. These changes, along with those presumably occurring at histones, produce a unique epigenetic signature in the CNS that regulates transcription of the genome and influences behavioral output.