Broad Epigenetic Signature of Maternal Care in the Brain of Adult Rats

BACKGROUND: Maternal care is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCORTICOID RECEPTOR) gene in the hippocampus of both rats and humans. In the rat, these effects are reversed by cross-fostering, demonstrating that they are defined by epigenetic rather than genetic processes. However, epigenetic changes at a single gene promoter are unlikely to account for the range of outcomes and the persistent change in expression of hundreds of additional genes in adult rats in response to differences in maternal care. METHODOLOGY/PRINCIPAL FINDINGS: We examine here using high-density oligonucleotide array the state of DNA methylation, histone acetylation and gene expression in a 7 million base pair region of chromosome 18 containing the NR3C1 gene in the hippocampus of adult rats. Natural variations in maternal care are associated with coordinate epigenetic changes spanning over a hundred kilobase pairs. The adult offspring of high compared to low maternal care mothers show epigenetic changes in promoters, exons, and gene ends associated with higher transcriptional activity across many genes within the locus examined. Other genes in this region remain unchanged, indicating a clustered yet specific and patterned response. Interestingly, the chromosomal region containing the protocadherin-α, -β, and -γ (Pcdh) gene families implicated in synaptogenesis show the highest differential response to maternal care. CONCLUSIONS/SIGNIFICANCE: The results suggest for the first time that the epigenetic response to maternal care is coordinated in clusters across broad genomic areas. The data indicate that the epigenetic response to maternal care involves not only single candidate gene promoters but includes transcriptional and intragenic sequences, as well as those residing distantly from transcription start sites. These epigenetic and transcriptional profiles constitute the first tiling microarray data set exploring the relationship between epigenetic modifications and RNA expression in both protein coding and non-coding regions across a chromosomal locus in the mammalian brain

Major depression epidemiology from a diathesis-stress conceptualization

<p>Abstract</p> <p>Background</p> <p>Major depression is a widely used diagnostic category but there is increasing dissatisfaction with its performance. The diathesis-stress model is an alternative approach that does not require the (sometimes arbitrary) imposition of categories onto the spectrum of depressive morbidity. However, application of this model has not been well explored and its consistency with available epidemiologic data is uncertain.</p> <p>Methods</p> <p>Simulation provides an opportunity to explore these issues. In this study, a simulation model based on an intuitive representation of diathesis-stress interaction was developed. Both diathesis and stress were represented using continuous distributions, without categorization. A diagnostic threshold was then applied to the simulation output to create nominal categories and to explore their consistency with available information.</p> <p>Results</p> <p>An apparently complex epidemiologic pattern emerged from the diathesis-stress interaction when thresholds were applied: incidence was time dependent, recurrence depended on the number of past episodes, baseline symptoms were associated with an increased risk of subsequent episodes and the remission rate declined with increasing episode duration.</p> <p>Conclusions</p> <p>A diathesis-stress conceptualization coupled with application of a threshold-based diagnostic definition may explain several of the apparent complexities of major depression epidemiology. Some of these complexities may be artifacts of the nominal diagnostic approach. These observations should encourage an empirical exploration of whether diathesis-stress interactions provide a more parsimonious framework for understanding depression than current approaches.</p