Stress dynamically regulates co-expression networks of glucocorticoid receptor-dependent MDD and SCZ risk genes

Zimmermann, Corinna; Arloth, Janine; Santarelli, Sara; Löschner, Anne; Weber, Peter; Schmidt, Mathias; Spengler, Dietmar; Binder, Elisabeth B.

doi:10.1038/s41398-019-0373-1

Cited by 14 publications

(9 citation statements)

References 45 publications

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“…Notably, clinical evidence shows that the vHPC, or the anterior hippocampal portion in humans, also modulates affective processes [8] associated with changes in brain volume, cell type [17], and gene expression [18]. Recently, we showed that stress induces greater alteration of gene expression change in the vHPC as opposed to the dorsal hippocampus [19] and others have characterized gene networks in the vHPC using disparate paradigms of stress [20][21][22]. However, genomic commonalities in the vHPC across multiple models of stress are largely uncharacterized.…”

Section: Introductionmentioning

confidence: 99%

Genomic modules and intramodular network concordance in susceptible and resilient male mice across models of stress

Caradonna

Zhang

O’Toole

et al. 2021

Neuropsychopharmacol.

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The multifactorial etiology of stress-related disorders necessitates a constant interrogation of the molecular convergences in preclinical models of stress that use disparate paradigms as stressors spanning from environmental challenges to genetic predisposition to hormonal signaling. Using RNA-sequencing, we investigated the genomic signatures in the ventral hippocampus common to mouse models of stress. Chronic oral corticosterone (CORT) induced increased anxiety- and depression-like behavior in wild-type male mice and male mice heterozygous for the gene coding for brain-derived neurotrophic factor Val66Met, a variant associated with genetic susceptibility to stress. In a separate set of male mice, chronic social defeat stress (CSDS) led to a susceptible or a resilient population, whose proportion was dependent on housing conditions, namely standard housing or enriched environment. Rank-rank-hypergeometric overlap (RRHO), a threshold-free approach that ranks genes by their p value and effect size direction, was used to identify genes from a continuous gradient of significancy that were concordant across groups. In mice treated with CORT and in standard-housed susceptible mice, differentially expressed genes (DEGs) were concordant for gene networks involved in neurotransmission, cytoskeleton function, and vascularization. Weighted gene co-expression analysis generated 54 gene hub modules and revealed two modules in which both CORT and CSDS-induced enrichment in DEGs, whose function was concordant with the RRHO predictions, and correlated with behavioral resilience or susceptibility. These data showed transcriptional concordance across models in which the stress coping depends upon hormonal, environmental, or genetic factors revealing common genomic drivers that embody the multifaceted nature of stress-related disorders.

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Section: Introductionmentioning

confidence: 99%

Genomic modules and intramodular network concordance in susceptible and resilient male mice across models of stress

Caradonna

Zhang

O’Toole

et al. 2021

Neuropsychopharmacol.

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“…Many psychiatric disorders are multifactorial and influenced by both genetic predisposition and environmental factors [70][71][72][73]. Adverse early life events have been associated with an increased risk of mood and anxiety disorders [74]; for example, genetic variants associated with schizophrenia interact with early life stress to affect risk [75]. Moreover, childhood stress increases the risk for later psychiatric disorders [11]: temporary childhood neglect is associated with an increased incidence of ADHD [76], and child abuse associates with suicidal ideation and various psychiatric disorders [77][78][79].…”

Section: Discussionmentioning

confidence: 99%

Altered hypothalamic DNA methylation and stress-induced hyperactivity in a novel model of early life stress

Fitzgerald

Sinton

Wernig-Zorc

et al. 2020

Preprint

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Early life stress during childhood is associated with a number of psychiatric disorders that manifest across the life course. Preterm birth is a profound stressor, and an important cause of cognitive impairment, as well as neurodevelopmental and psychiatric disorders. However, the mechanisms that link events during the early neonatal period with later functional problems are poorly understood. We developed a novel mouse model of early life stress (modified maternal separation; MMS) with specific relevance to preterm birth (PTB) and hypothesised it would affect the hypothalamic transcriptome and DNA methylome and impact on behaviour in adulthood. MMS consisted of repeatedly stimulating pups for 1.5 hours/day, whilst separated from their mother, from postnatal day (P)4-6. 3' RNA sequencing and DNA methylation immunoprecipitation (meDIP) sequencing was performed on the hypothalamus at P6. Behaviour was assessed with the elevated plus and open field mazes, and in-cage monitoring at 3-4 months of age. Although MMS was only associated with subtle changes in gene expression there were widespread alterations in DNA methylation. Notably, differentially methylated regions were enriched for synapse-associated loci. MMS also resulted in hyperactivity in the elevated plus and open field mazes, but in-cage monitoring revealed that this was not representative of habitual hyperactivity. In conclusion we describe a novel model of early life stress with relevance to PTB, with marked effects on DNA methylation in the hypothalamus and with stress-specific hyperactivity in young adulthood. We suggest that these results have implications for the understanding of early life stress mediated effects on brain development.

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“…The eQTL transcripts (etranscripts) regulated by these variants form tight co-expression networks. Using an animal model of exposure to adversity across development (Santarelli et al, 2017), we observed that different combinations of early and adult environments (supportive vs. stressful) substantially affect co-expression structure of these networks in a highly brain region-specific manner (Zimmermann et al, 2019). However, this set of eQTLs and regulated etranscripts was identified in a male only cohort.…”

Section: Introductionmentioning

confidence: 99%

Sex differences in the genetic regulation of the blood transcriptome response to glucocorticoid receptor activation

Moore

Halldorsdottir

Martins

et al. 2020

Preprint

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Substantial sex differences have been reported in the physiological response to stress at multiple levels, including the release of the stress hormone, cortisol. How these differences relate to differential risks for stress-related psychiatric disorders is still poorly understood. We have previously identified genomic variants in males regulating the initial transcriptional response to cortisol via glucocorticoid receptor (GR) activation, and these variants are associated with risk for major depressive disorder (MDD) and other psychiatric disorders. Here, we extend these investigations to a sample of males and females in order to examine sex-biased genetic regulation of the transcriptional response to the stress hormone. Gene expression levels in peripheral blood were obtained before and after GRstimulation with the selective GR agonist dexamethasone to identify differential expression following GR-activation (GR-DE) in 93 women and 196 men. We first explored sex differences in the transcriptional GR-response followed by the identification of sex-biased expression quantitative trait loci (eQTLs) by associating gene expression and genotype data stratified by sex. While GR-response transcripts mostly overlapped between males and females, GRresponse eQTLs showed strong sex-bias. A total of 804 significant GR-response cis-eQTL bins were found in the joint sample, 648 in females only, and 705 in males only. However, only 46 sex-biased GR-eQTL transcripts (etranscripts) overlapped between the sexes. The sets of associated sex-biased GR eQTL SNPs (eSNPs) were located in different functional genomic elements. Male and female sex-biased etranscripts were enriched within postmortem brain transcriptional profiles associated with MDD specifically in males and females in the cingulate cortex but not other brain regions. Female-biased GR-eSNPs were enriched among SNPs linked to MDD in genome wide association studies (GWAS). Finally, transcriptional sensitive genetic profile scores indexing sex-biased larger transcriptional changes to GRstimulation were predictive of depression status and depressive symptoms in a sexconcordant manner in a child and adolescent cohort (n = 584). Taken together, while the GR-DE effects were similar between females and males, the genetic moderation of these effects was highly sex-biased and associated with depressionrelated molecular profiles and symptoms in a similarly sex-biased manner. These results suggest potential of GR-response eQTLs as sex-biased biomarkers of risk for stress-related psychiatric disorders.

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Stress dynamically regulates co-expression networks of glucocorticoid receptor-dependent MDD and SCZ risk genes

Cited by 14 publications

References 45 publications

Genomic modules and intramodular network concordance in susceptible and resilient male mice across models of stress

Genomic modules and intramodular network concordance in susceptible and resilient male mice across models of stress

Altered hypothalamic DNA methylation and stress-induced hyperactivity in a novel model of early life stress

Sex differences in the genetic regulation of the blood transcriptome response to glucocorticoid receptor activation

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