Cell-type-specific epigenetic effects of early life stress on the brain

Abstract

Early life stress (ELS) induces long-term phenotypic adaptations that contribute to increased vulnerability to a host of neuropsychiatric disorders. Epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNA, are a proposed link between environmental stressors, alterations in gene expression, and phenotypes. Epigenetic modifications play a primary role in shaping functional differences between cell types and can be modified by environmental perturbations, especially in early development. Together with contributions from genetic variation, epigenetic mechanisms orchestrate patterns of gene expression within specific cell types that contribute to phenotypic variation between individuals. To date, many studies have provided insights into epigenetic changes resulting from ELS. However, most of these studies have examined heterogenous brain tissue, despite evidence of cell-type-specific epigenetic modifications in phenotypes associated with ELS. In this review, we focus on rodent and human studies that have examined epigenetic modifications induced by ELS in select cell types isolated from the brain or associated with genes that have cell-type-restricted expression in neurons, microglia, astrocytes, and oligodendrocytes. Although significant challenges remain, future studies using these approaches can enable important mechanistic insight into the role of epigenetic variation in the effects of ELS on brain function.

Fig. 1. Timeline of cellular programming in the brain and windows of susceptibility for epigenetic effects by early life stress (ELS).

Early to mid-gestation, neural stem cells produce neuronal progenitors, precursors for neurons, which migrate and form synapses from mid-gestation to toddler/weanling age. Synaptogenesis starts mid-gestation, peaks in toddler/weanling age, and continues throughout life. In late gestation to toddler/weanling age, neural stem cells give rise to glial progenitors, precursors for astrocytes and oligodendrocytes, which mature from birth to toddler/weanling age. In early and mid-gestation, myeloid-derived macrophages invade the embryonic nervous system to become microglia, which mature into the neonatal period. Microglia and glia continue to have local self-renewal and proliferative capacity into adulthood. Overall, during these periods of cellular production and maturation, ELS factors (e.g. stress hormones, immune stimulants) can alter cell type proportions as well as induce epigenetic reprogramming, leading to long-term changes in the brain. E = embryonic day, P = post-natal day.

Fig. 2. Limitations of examining heterogenous brain tissue for measuring epigenetic modifications.

A Group differences in the epigenetic mark of a particular gene are not indicative of which cell type(s) are responsible for driving these changes. B Group differences in the epigenetic mark of a particular gene may be masked by differences in cell type proportions between groups.