Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation

Abstract

Resilience and susceptibility to stress and diseases exert pervasive impacts on human well-being. Such impacts have typically been studied in psychological and sociological contexts, whereby genetic and ecological factors mediate levels and directions of responses to diverse stressors during development. Ultimately, however, such responses are determined at the cellular level, through geneby-environment and epigenetic interactions that involve trade-offs between different cellular pathways and functions. The purpose of this project is to develop the first cellular-level models of human resilience and susceptibility to external stimuli. These models will permit the molecular-genetic, epigenetic and computational dissection of the mechanisms involved in differential susceptibility to both negative and positive environmental impacts. Mechanistically, CRISPR/cas9 gene editing technology will be used to engineer human neuronal cell lines to express a set of alleles, for known loci, that are associated with extreme high to extreme low susceptibility to negative and positive environments. These differential susceptibility cell lines will be subjected to stress-and benefit-associated perturbations, with outcomes quantified in terms of (a) epigenomic profiles of methylation and histone modifications, (b) gene expression, and (c) cellular-level phenotypes such as growth and survival to identify relevant gene co-regulation networks underlying genetic susceptibility. This experimental paradigm will allow molecular elucidation of the mechanisms of differential susceptibility to stimuli, based on a detailed analysis of the nature and roles of molecular and cellular level trade-offs in physiological function. This project will develop new computational and statistical methods to address the challenges posed by the complex gene-by-environment interactions in these data sets. This interdisciplinary work is novel and high risk because no previous studies have sought to recapitulate differential susceptibility effects combining multiple genetic modifications in a cellular system. It is potentially transformative in that it aims to open up a new experimental paradigm for analyzing the impact of external stimuli, though psychologically and disease-informed genetic modifications that can be subject to multilevel omics analyses in the context of the relevant ecologicalevolutionary theory regarding trade-offs.

FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells – First insights from novel humanized mice

“…Early life adversity has been discussed to prime the stress response systems to pathological processes (Ganguly & Brenhouse, 2015;Jens & Zakreski, 2015;Kompier et al, 2019;Lesuis et al, 2018Lesuis et al, , 2019Vaiserman & Koliada, 2017) and astrocytes were reported to be involved in the early programming of stress responsivity (Abbink et al, 2019;Gunn et al, 2013;Saavedra et al, 2017). During neuronal development, demethylation of the FKBP5 locus as consequence of glucocorticoid exposure was reported (Provençal et al, 2019) and if the same holds true for astrocytes, allele-specific methylation changes in FKBP5 could exacerbate the observed FKBP5-SNP-associated differences in glucocorticoid reactivity. These data provide a first indication that differential stress sensitivity via astrocytic signaling could play a role in pathology linked to FKBP5 SNPs.…”

Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation

“…GSE119842 and GSE119843) and HPC methylation data (accession no. GSE119846) were deposited in the Gene Expression Omnibus repository (37).…”

Promoter Methylation Changes in the Placental DIO3 and CRH Genes Are Involved in the Second Trimester Maternal Depression Induced Preterm Birth and Small for Gestational Age Birth

“…Cortisol can stimulate production of CRH in the placenta (27). Epigenetic mechanisms have been suggested to mediate the lasting molecular embedding of exposures to abnormal cortisol and CRH levels (28). In this study, increased methylation of the placental CRH gene may be one of the indications that maternal depression during pregnancy causes changes in placental hormones.…”