Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus

Abstract

Early life experience is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCOR-TICOID RECEPTOR) gene in the hippocampus of both rats and humans. However, it is unlikely that such effects completely capture the evolutionarily conserved epigenetic mechanisms of early adaptation to environment. Here we present DNA methylation profiles spanning 6.5 million base pairs centered at the NR3C1 gene in the hippocampus of humans who experienced abuse as children and nonabused controls. We compare these profiles to corresponding DNA methylation profiles in rats that received differential levels of maternal care. The profiles of both species reveal hundreds of DNA methylation differences associated with early life experience distributed across the entire region in nonrandom patterns. For instance, methylation differences tend to cluster by genomic location, forming clusters covering as many as 1 million bases. Even more surprisingly, these differences seem to specifically target regulatory regions such as gene promoters, particularly those of the protocadherin α, β, and γ gene families. Beyond these high-level similarities, more detailed analyses reveal methylation differences likely stemming from the significant biological and environmental differences between species. These results provide support for an analogous cross-species epigenetic regulatory response at the level of the genomic region to early life experience.conservation | neuronal plasticity V ariation in early life experience is associated with differences in life-long health and behavioral trajectories in animals as well as humans. For example, differences in maternal care in rats during the first week of life are associated with long-term effects on behavior and brain function that persist into adulthood, including alterations in the stress response (1). In humans, similar effects are observed. For instance, childhood maltreatment associates with development of both externalizing and internalizing personality traits and psychopathology in adulthood (2). The association in both rats and humans of stable developmental phenotypes with early life experience suggests that molecular mechanisms may serve as a memory of these early life experiences in both species. In fact, there is evidence that these long-term effects are, at least in part, mediated by epigenetic alterations in the brain. In particular, recent studies have found aberrant DNA methylation in the NR3C1 (GLUCOCORTICOID RECEPTOR) gene promoter of the hippocampi of both rats and humans associated with differential early life experience (3, 4). Exposure of infant rats to stressed caretakers displaying abusive behavior produced persisting changes in methylation of the BDNF gene promoter in the adult prefrontal cortex (5). Early life stress in mice caused sustained DNA hypomethylation of an important regulatory region of the AVP gene (6).Although explanations involving a single site are appealing, it is unlikely that the broad systemic response to early life experien...

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