Environmentally Malleable Epigenomic Regions In The Mammalian Brain

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Understanding the development of epigenetic patterns that underlie neural development and differentiation is an essential foundation for understanding what occurs in “abnormal” situations. DNA methylation, in concert with other epigenetic regulators, controls the accessibility of transcription factors to DNA and/or their function. While extensively studied in neuronal progenitors in vitro, the role of methylation/demethylation in neuronal lineage/subtype specification in vivo is not known. By profiling two distinct neuronal lineages, and five neuron subtypes in the hippocampus and striatum, we uncovered a set of five principles that govern DNA methylation-dynamics in neurodevelopment. By dividing neurodevelopment to three alternating methylation and demethylation periods and applying the principles to each of these stages, we created a matrix that comprehensively describes the targets, genomic contexts, functional consequences and putative mechanisms of methylation/demethylation events. The overarching theme is that the developmental methylation program is remarkably similar in the hippocampus and striatum, with significant divergence only occurring during subtype specification. Our matrix can be cross-referenced with disease-associated methylation changes to specify possible events and underlying principles compromised in disease. Adverse environmental conditions, particularly during early life, are associated with increased risk for behavioral and/or psychiatric disorders. However, the molecular basis that can potentially link environmental conditions to psychopathologies are unknown, complicating diagnosis and therapeutic measures. We identified differentially methylated regions (DMRs) in mammalian offspring exposed to an adverse maternal environment associated with anxiety in both the mother and offspring. We hypothesized the presence of metastable “hotspots” in the genome that display an inherent sensitivity to environmental cues. These hotspots would enable an adaptive/maladaptive molecular response to multiple environmental conditions by modifying appropriate gene expression patterns and cellular phenotypes. Using several animal models of early life adversities, which result in a common offspring anxiety phenotype, we used genome-wide DNA methylation sequencing to detect common environmentally sensitive DMRs (E-DMRs). E-DMRs displayed several DNA features including: Exonic enrichment, intermediate methylation, and enhancer activity. Interestingly, E-DMRs did not perturb the overall patterning of DNA methylation that takes place during neural development. The experience dependent variations in DNA methylation at E-DMRs may prime the genome for differential transcriptional response to later events. This metaplasticity may be especially important in brain regions responsible for processing environmental input to elicit a behavioral response. Since maternal conditions impact the offspring during gametogenesis and through fetal/early-postnatal life, the resultant phenotype is likely the aggregate of consecutive germline and somatic effects; a concept that hasn’t been previously studied. We dissected a complex maternally-transmitted phenotype, reminiscent of comorbid generalized anxiety/depression, to elementary behaviors/domains and their transmission mechanisms. We show that four anxiety/stress-reactive traits are transmitted via independent iterative-somatic and gametic epigenetic mechanisms across multiple generations. Somatic/gametic transmission alters DNA methylation at enhancers within synaptic genes whose functions can be linked to the behavioral-traits. Traits have generation-dependent penetrance and sex-specificity resulting in pleiotropy, often seen in psychiatry. A transmission-pathway based concept can refine current inheritance models of psychiatric diseases and facilitate the development of better animal models and new therapeutic approaches.

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Molecular Biology

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Doctor of Philosophy

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Attribution-NonCommercial-NoDerivatives 4.0 International


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