Anxiety Associated Increased CpG Methylation in the Promoter of Asb1: A Translational Approach Evidenced by Epidemiological and Clinical Studies and a Murine Model

Epigenetic regulation in anxiety is suggested, but evidence from large studies is needed. We conducted an epigenome-wide association study (EWAS) on anxiety in a population-based cohort and validated our finding in a clinical cohort as well as a murine model. In the KORA cohort, participants (n= 1522, age 32–72 years) were administered the Generalized Anxiety Disorder (GAD-7) instrument, whole blood DNA methylation was measured (Illumina 450K BeadChip), and circulating levels of hs-CRP and IL-18 were assessed in the association between anxiety and methylation. DNA methylation was measured using the same instrument in a study of patients with anxiety disorders recruited at the Max Planck Institute of Psychiatry (MPIP, 131 non-medicated cases and 169 controls). To expand our mechanistic understanding, these findings were reverse translated in a mouse model of acute social defeat stress. In the KORA study, participants were classified according to mild, moderate, or severe levels of anxiety (29.4%/6.0%/1.5%, respectively). Severe anxiety was associated with 48.5% increased methylation at a single CpG site (cg12701571) located in the promoter of the gene encoding Asb1 (β-coefficient = 0.56 standard error (SE) =0.10, p (Bonferroni) = 0.005), a protein hypothetically involved in regulation of cytokine signaling. An interaction between IL-18 and severe anxiety with methylation of this CpG cite showed a tendency towards significance in the total population (p =0.083) and a significant interaction among women (p =0.014). Methylation of the same CpG was positively associated with Panic and Agoraphobia scale (PAS) scores (β= 0.005, SE= 0.002, p=0.021, n= 131) among cases in the MPIP study. In a murine model of acute social defeat stress, Asb1 gene expression was significantly upregulated in a tissue-specific manner (p= 0.006), which correlated with upregulation of the neuroimmunomodulating cytokine interleukin 1 beta. Our findings suggest epigenetic regulation of the stress-responsive Asb1 gene in anxiety-related phenotypes. Further studies are necessary to elucidate the causal direction of this association and the potential role of Asb1-mediated immune dysregulation in anxiety disorders

Prenatal adverse environment is associated with epigenetic age deceleration at birth and hypomethylation at the hypoxia-responsive EP300 gene

Abstract Background: Obstetric complications have long been retrospectively associated with a wide range of short- and long-term health consequences, including neurodevelopmental alterations such as those observed in schizophrenia and other psychiatric disorders. However, prospective studies assessing fetal well-being during pregnancy tend to focus on perinatal complications as the final outcome of interest, while there is a scarcity of postnatal follow-up studies. In this study, the cerebroplacental ratio (CPR), a hemodynamic parameter reflecting fetal adaptation to hypoxic conditions, was analyzed in a sample of monozygotic monochorionic twins (60 subjects), part of them with prenatal complications, with regard to (i) epigenetic age acceleration, and (ii) DNA methylation at genes included in the polygenic risk score (PRS) for schizophrenia, and highly expressed in placental tissue. Results: Decreased CPR measured during the third trimester was associated with epigenetic age deceleration (β = 0.21, t = 3.362, p = 0.002). Exploration of DNA methylation at placentally expressed genes of the PRS for schizophrenia revealed methylation at cg06793497 (EP300 gene) to be associated with CPR (β = 0.021, t = 4.385; p = 0.00008, FDR-adjusted p = 0.11). This association was reinforced by means of an intrapair analysis in monozygotic twins discordant for prenatal suffering (β = 0.027, t = 3.924, p = 0.001). Conclusions: Prenatal adverse environment during the third trimester of pregnancy is associated with both (i) developmental immaturity in terms of epigenetic age, and (ii) decreased CpG-specific methylation in a gene involved in hypoxia response and schizophrenia genetic liability. Keywords: DNA methylation, Obstetric complications, Prenatal stress, Hypoxia, EP300 gene, Epigenetic clock, Monozygotic twins, Schizophreni

SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection

Autophagy is an essential cellular process affecting virus infections and other diseases and Beclin1 (BECN1) is one of its key regulators. Here, we identified S-phase kinase-associated protein 2 (SKP2) as E3 ligase that executes lysine-48-linked poly-ubiquitination of BECN1, thus promoting its proteasomal degradation. SKP2 activity is regulated by phosphorylation in a hetero-complex involving FKBP51, PHLPP, AKT1, and BECN1. Genetic or pharmacological inhibition of SKP2 decreases BECN1 ubiquitination, decreases BECN1 degradation and enhances autophagic flux. Middle East respiratory syndrome coronavirus (MERS-CoV) multiplication results in reduced BECN1 levels and blocks the fusion of autophagosomes and lysosomes. Inhibitors of SKP2 not only enhance autophagy but also reduce the replication of MERS-CoV up to 28,000-fold. The SKP2-BECN1 link constitutes a promising target for host-directed antiviral drugs and possibly other autophagy-sensitive conditions

Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-kappa B-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-kappa B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-kappa B. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-kappa B through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-kappa B signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities

Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappa B-driven inflammation and cardiovascular risk

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-kappa B-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-kappa B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-kappa B. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-kappa B through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-kappa B signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.Peer reviewe

Glucocorticoid signaling drives epigenetic and transcription factors to induce key regulators of human parturition

Glucocorticoids are thought to play an important role in parturition. Two recent articles by Di Stefano et al. in the Archives and Wang et al. in this issue of Science Signaling reveal novel mechanisms by which glucocorticoid signaling can drive the epigenetic and transcriptional machinery to induce molecules involved in parturition, including the neuropeptide corticotropin-releasing hormone (CRH), the enzyme cyclooxygenase-2 (COX-2), and the autacoid hormone prostaglandin E-2. These findings contribute to our understanding of how glucocorticoids may regulate human parturition

Genomics of PTSD

This chapter summarizes available literature on the genetics of posttraumatic stress disorder (PTSD) and highlights scientific research in animal models and humans related to the identification of genetic risk factors for PTSD. Since trauma exposure is a prerequisite for diagnosis of PTSD, the chapter discusses how genetic predisposition can moderate the environmental impact on disease. It presents an overview of candidate-based and genome-wide association studies as well as gene-environment interaction studies performed in humans to date. Additionally, the chapter describes potential epigenetic mechanisms in tandem with gene expression results that provide new models for how the environment influences PTSD risk by modification of genetic contributions to PTSD. Future studies offer a systems-level understanding of how multiple genes and biological pathways interact with traumatic events to determine distinct outcomes among individuals. Such integrative studies pave the way for a better understanding of genomics and subsequently treatment of PTSD.</p

Genomics of PTSD

This chapter summarizes available literature on the genetics of posttraumatic stress disorder (PTSD) and highlights scientific research in animal models and humans related to the identification of genetic risk factors for PTSD. Since trauma exposure is a prerequisite for diagnosis of PTSD, the chapter discusses how genetic predisposition can moderate the environmental impact on disease. It presents an overview of candidate-based and genome-wide association studies as well as gene-environment interaction studies performed in humans to date. Additionally, the chapter describes potential epigenetic mechanisms in tandem with gene expression results that provide new models for how the environment influences PTSD risk by modification of genetic contributions to PTSD. Future studies offer a systems-level understanding of how multiple genes and biological pathways interact with traumatic events to determine distinct outcomes among individuals. Such integrative studies pave the way for a better understanding of genomics and subsequently treatment of PTSD.</p