Impact of Early life MetaBolic and psychosocial strEss on susceptibility to mental Disorders; from converging epigenetic signatures to novel targets for therapeutic intervention

Scientific abstract of the project

Nearly 40% of the EU population each year suffers from a mental disorder. Adverse experiences early in life can produce important physiological changes, which become embedded biological traces leading to increased vulnerability for later depression. There is now robust evidence indicating that early metabolic challenges impinge upon energy balance regulatory systems, which, in many cases, overlap with stress-response systems. EMBED will identify informative DNA methylation differences associated with prenatal psychological and metabolic stressors in genes that are relevant for mood disorders. These will be related to shared biomarkers to define common biological substrates between early life stress and maternal obesity for prevention and treatment. We will also determine whether intervention strategies can reverse such epigenetic marks and related biomarkers. The relationship between DNA methylation pattern in human peripheral samples (cord blood) and brain will be studied in animal models and brain post-mortem samples from depressive patients. EMBED brings together leading researchers with complementary expertise to exploit existing clinical data sets, including biomaterial collections from previous collaborative proposals, that will be analyzed in an original and innovative way to study the role of different, but often co-occurring, adverse prenatal conditions on individual risk/resilience to develop mental disorders in adulthood. This research may lead not only to a better understanding of the risk architecture of major psychiatric disorders, but could also enable preventive measures in risk populations, new diagnostics and, potentially, therapeutic approaches since, in contrast to genetic variations, epigenetic effects on the transcriptome may be reversed, also in adulthood.

Objectives

The primary objectives of this work are to:

Assess shared epigenetic mechanisms of maternal stress and maternal obesity through DNA methylation analysis and discovery in children born to stressed or obese mothers as well as adult post-mortem brains from people whose mothers were stressed or obese;
Test shared biological mechanisms mediating psychological stress and metabolic stress through metabolome and transcriptome analysis in two mother/infant cohorts;
Define the epigenetic signature of disease reversibility;
Delineate epigenetic signatures predicting high risk of depression for early prevention; and
Discover novel genes that respond both to maternal stress and maternal obesity.

As secondary objectives, the project aims to also:

Characterize the stability of methylation profiles of candidate genes between birth and later points in life; and
Establish the level of correspondence in methylation profiles of genes between brain and peripheral white blood cells at birth and later in life.

Layman summary

Extensive research on the biology of stress now shows that healthy development can be derailed by excessive or prolonged activation of stress response systems in the body and brain during fetal life. Such toxic stress exposure can have damaging effects on learning, behavior, and mental health across the lifespan. The consortium has been built to integrate basic researchers and clinicians to work on two very relevant cohorts (offspring of obese or stressed mothers) that will be here combined in a very innovative way to address specific questions on mental health risk factors and their potential prevention. One main concept is that maternal obesity during prenatal life can trigger similar responses to maternal stress, altering developmental trajectories and increasing the risk for mental health at adulthood. It is hypothesized that maternal stress might be accompanied by inappropriate nutrition patterns which could synergize in activating stress-response systems in the developing organism. These adverse experiences can increase the likelihood of developmental delays and later health problems, including heart disease, diabetes, and depression.

This consortium will assess whether common biological signals characterise early exposure to metabolic and psychological stress, affecting the long-term expression of genes involved in brain as well as in immune-metabolic function, triggering mental disorders. A special emphasis will be given to long-lasting epigenetic modifications, which could alter context- and time-dependent expression of genes relevant for brain function as well as peripheral hormones, cytokines or adipokines, indices of immune-metabolic function, that might be used in the clinic for disease prevention and health promotion during pregnancy.

Project publications

https://pubmed.ncbi.nlm.nih.gov/31852885
Longitudinal transcriptome-wide gene expression analysis of sleep deprivation treatment shows involvement of circadian genes and immune pathways

Jerome C. Foo, Nina Trautmann, Carsten Sticht, Jens Treutlein, Josef Frank, Fabian Streit, Stephanie H. Witt, Carolina De La Torre, Steffen Conrad von Heydendorff, Lea Sirignano, Junfang Chen, Bertram Müller-Myhsok, Andreas Meyer-Lindenberg, Christian C. Witt, Maria Gilles, Michael Deuschle & Marcella Rietschel

Transl Psychiatry, 2019, 9:343.

Abstract: Therapeutic sleep deprivation (SD) rapidly induces robust, transient antidepressant effects in a large proportion of major mood disorder patients suffering from a depressive episode, but underlying b ... iological factors remain poorly understood. Research suggests that these patients may have altered circadian molecular genetic 'clocks' and that SD functions through 'resetting' dysregulated genes; additional factors may be involved, warranting further investigation. Leveraging advances in microarray technology enabling the transcriptome-wide assessment of gene expression, this study aimed to examine gene expression changes accompanying SD and recovery sleep in patients suffering from an episode of depression. Patients (N = 78) and controls (N = 15) underwent SD, with blood taken at the same time of day before SD, after one night of SD and after recovery sleep. A transcriptome-wide gene-by-gene approach was used, with a targeted look also taken at circadian genes. Furthermore, gene set enrichment, and longitudinal gene set analyses including the time point after recovery sleep, were conducted. Circadian genes were significantly affected by SD, with patterns suggesting that molecular clocks of responders and non-responders, as well as patients and controls respond differently to chronobiologic stimuli. Notably, gene set analyses revealed a strong widespread effect of SD on pathways involved in immune function and inflammatory response, such as those involved in cytokine and especially in interleukin signalling. Longitudinal gene set analyses showed that in responders these pathways were upregulated after SD; in non-responders, little response was observed. Our findings emphasize the close relationship between circadian, immune and sleep systems and their link to etiology of depression at the transcriptomic level.
https://pubmed.ncbi.nlm.nih.gov/32080920
Acute alcohol withdrawal and recovery in men lead to profound changes in DNA methylation profiles - a longitudinal clinical study

Stephanie H. Witt, Josef Frank, Ulrich Frischknecht, Jens Treutlein, Fabian Streit, Jerome C. Foo, Lea Sirignano, Helene Dukal, Franziska Degenhardt , Anne Koopmann, Sabine Hoffmann , Gabi Koller, Oliver Pogarell, Ulrich W. Preuss, Peter Zill, Kristina Adorjan, Thomas G. Schulze, Markus Nöthen, Rainer Spanagel, Falk Kiefer, Marcella Rietschel

Addiction, 2020, 115:2034-2044.

Abstract: Background and aims: Withdrawal is a serious and sometimes life-threatening event in alcohol-dependent individuals. It has been suggested that epigenetic processes may play a role in this context. Th ... is study aimed to identify genes and pathways involved in such processes which hint to relevant mechanisms underlying withdrawal. Design: Cross-sectional case-control study and longitudinal within-cases study during alcohol withdrawal and after 2 weeks of recovery SETTING: Addiction medicine departments in two university hospitals in southern Germany. Participants/cases: Ninety-nine alcohol-dependent male patients receiving in-patient treatment and suffering from severe withdrawal symptoms during detoxification and 95 age-matched male controls. Measurements: Epigenome-wide methylation patterns were analyzed in patients during acute alcohol withdrawal and after 2 weeks of recovery, as well as in age-matched controls using Illumina EPIC bead chips. Methylation levels of patients and controls were tested for association with withdrawal status. Tests were adjusted for technical and batch effects, age, smoking and cell type distribution. Single-site analysis, as well as an analysis of differentially methylated regions and gene ontology analysis, were performed. Findings: We found pronounced epigenome-wide significant [false discovery rate (FDR) < 0.05] differences between patients during withdrawal and after 2 weeks [2876 cytosine-phosphate-guanine (CpG) sites], as well as between patients and controls (9845 and 6094 CpG sites comparing patients at time-point 1 and patients at time-point 2 versus controls, respectively). Analysis of differentially methylated regions and involved pathways revealed an over-representation of gene ontology terms related to the immune system response. Differences between patients and controls diminished after recovery (> 800 CpG sites less), suggesting a partial reversibility of alcohol- and withdrawal-related methylation. Conclusions: Acute alcohol withdrawal in severely dependent male patients appears to be associated with extensive changes in epigenome-wide methylation patterns. In particular, genes involved in immune system response seem to be affected by this condition.
https://pubmed.ncbi.nlm.nih.gov/32032668
Maternal Obesity as a Risk Factor for Brain Development and Mental Health in the Offspring

Cirulli F, Musillo, C. Berry A.

Neuroscience, 2020, 447:122-135.

Abstract: Maternal obesity plays a key role in the health trajectory of the offspring. Although research on this topic has largely focused on the potential of this condition to increase the risk for child obes ... ity, it is becoming more and more evident that it can also significantly impact cognitive function and mental health. The mechanisms underlying these effects are starting to be elucidated and point to the placenta as a critical organ that may mediate changes in the response to stress, immune function and oxidative stress. Long-term effects of maternal obesity may rely upon epigenetic changes in selected genes that are involved in metabolic and trophic regulations of the brain. More recent evidence also indicates the gut microbiota as a potential mediator of these effects. Overall, understanding cause-effect relationships can allow the development of preventive measures that could rely upon dietary changes in the mother and the offspring. Addressing diets appears more feasible than developing new pharmacological targets and has the potential to affect the multiple interconnected physiological pathways engaged by these complex regulations, allowing prevention of both metabolic and mental disorders.
https://pubmed.ncbi.nlm.nih.gov/32792995/
Association of Locomotor Activity During Sleep Deprivation Treatment With Response

Jerome Clifford Foo, Lea Sirignano, Nina Trautmann, Jinhyuk Kim, Stephanie H Witt, Fabian Streit, Josef Frank, Lea Zillich, Andreas Meyer-Lindenberg, Ulrich Ebner-Priemer, Claudia Schilling, Michael Schredl, Yoshiharu Yamamoto, Maria Gilles, Michael Deuschle, Marcella Rietschel

Front Psychiatry, 2020, 11:688.

Abstract: Disrupted circadian rhythms and sleep patterns are frequently observed features of psychiatric disorders, and especially mood disorders. Sleep deprivation treatment (SD) exerts rapid but transient an ... tidepressant effects in depressed patients and has gained recognition as a model to study quick-acting antidepressant effects. It is of interest how locomotor activity patterns during SD might be associated with and potentially predict treatment response. The present study is an analysis of locomotor activity data, previously collected over a 24 h period, to examine the night of SD (Trautmann et al. 2018) as mood disorder patients suffering from a depressive episode (n = 78; after exclusions n = 59) underwent SD. In this exploratory analysis, the associations between response to SD, locomotor activity, and subjective mood during the 24 h period of SD were explored. Higher levels of activity overall were observed in non-responders (n = 18); in particular, non-responders moved more during the evening of SD until midnight and remained high thereafter. In contrast, activity in responders (n = 41) decreased during the evening and increased in the morning. Subjective mood was not found to be associated with locomotor activity. The window of data available in this analysis being limited, additional data from before and after the intervention are required to fully characterize the results observed. The present results hint at the possible utility of locomotor activity as a predictor and early indicator of treatment response, and suggest that the relationship between SD and locomotor activity patterns should be further investigated.
https://pubmed.ncbi.nlm.nih.gov/33344724/
Long-term effects of stress early in life on microRNA-30a and its network: Preventive effects of lurasidone and potential implications for depression vulnerability

Annamaria Cattaneo, Matthew Suderman, Nadia Cattane, Monica Mazzelli, Veronica Begni, Carlo Maj, Ilari D'Aprile, Carmine M Pariante, Alessia Luoni, Alessandra Berry, Katharina Wurst, Leif Hommers, Katharina Domschke, Francesca Cirulli, Moshe Szyf1, Andreas Menke, Marco A Riva

Neurobiol Stress, 2020, 13:100271.

Abstract: Exposure to early life stress can interfere with neurodevelopmental trajectories to increase the vulnerability for psychiatric disorders later in life. With this respect, epigenetic mechanisms play a ... key role for the long-lasting changes in brain functions that may elicit and sustain psychopathologic outcomes. Here, we investigated DNA methylation changes as possible epigenetic mechanism mediating the effect of prenatal stress (PNS), an experimental paradigm associated with behavioral and molecular alterations relevant for psychiatric disorders. We identified 138 genes as being differentially methylated in the prefrontal cortex (PFC) and in the hippocampus (HIP) of male and female adult rats exposed to PNS. Among these genes, miR-30a and Neurod1 emerged as potential players for the negative outcomes associated with PNS exposure. Indeed, in addition to showing consistent methylation differences in both brain regions and in both sexes, and interacting with each other, they are both involved in Axon guidance and Neurotrophin signaling, which are important to neurodevelopmental disorders. We also found a significant reduction in the expression of a panel of genes (CAMK2A, c-JUN, LIMK1, MAP2K1, MAP2K2, PIK3CA and PLCG1) that belong to these two biological pathways and are also validated targets of miR-30a, pointing to a down-regulation of these pathways as a consequence of PNS exposure. Interestingly, we also found that miR-30a levels were significantly upregulated in depressed patients exposed to childhood trauma, as compared to control individuals. Importantly, we also found that a sub-chronic treatment with the atypical antipsychotic drug, lurasidone, during adolescence was able to prevent the up-regulation of miR-30a and normalized the expression of its target genes in response to PNS exposure. Our results demonstrate that miR-30a undergoes epigenetic changes following early life stress exposure and suggest that this miRNA could play a key role in producing broad and long-lasting alterations in neuroplasticity-related pathways, contributing to the etiology of psychiatric disorders.