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.