The HAPSTR2 retrogene buffers stress signaling and resilience in mammals
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ABSTRACT:
PROVIDER: PRJNA907726 | ENA |
REPOSITORIES: ENA
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Project description:We recently identified HAPSTR1 (C16orf72) as a key component in a novel pathway which regulates the cellular response to molecular stressors, such as DNA damage, nutrient scarcity, and protein misfolding. Here, we identify a functional paralog to HAPSTR1: HAPSTR2. HAPSTR2 formed early in mammalian evolution, via genomic integration of a reverse transcribed HAPSTR1 transcript, and has since been preserved under purifying selection. HAPSTR2, expressed primarily in neural and germline tissues and a subset of cancers, retains established biochemical features of HAPSTR1 to achieve two functions. In normal physiology, HAPSTR2 directly interacts with HAPSTR1, markedly augmenting HAPSTR1 protein stability in a manner independent from HAPSTR1's canonical E3 ligase, HUWE1. Alternatively, in the context of HAPSTR1 loss, HAPSTR2 expression is sufficient to buffer stress signaling and resilience. Thus, we discover a mammalian retrogene which safeguards fitness.
2023-01-18 | GSE219209 | GEO
Project description:We recently identified HAPSTR1 (C16orf72) as a key component in a novel pathway which regulates the cellular response to molecular stressors, such as DNA damage, nutrient scarcity, and protein misfolding. Here, we identify a functional paralog to HAPSTR1: HAPSTR2. HAPSTR2 formed early in mammalian evolution, via genomic integration of a reverse transcribed HAPSTR1 transcript, and has since been preserved under purifying selection. HAPSTR2, expressed primarily in neural and germline tissues and a subset of cancers, retains established biochemical features of HAPSTR1 to achieve two functions. In normal physiology, HAPSTR2 directly interacts with HAPSTR1, markedly augmenting HAPSTR1 protein stability in a manner independent from HAPSTR1's canonical E3 ligase, HUWE1. Alternatively, in the context of HAPSTR1 loss, HAPSTR2 expression is sufficient to buffer stress signaling and resilience. Thus, we discover a mammalian retrogene which safeguards fitness.
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Project description:Individuals in a population respond differently to stressful situations. While resilient individuals recover efficiently, others are susceptible to the same stressors. Most existing information regarding the factors regulating stress resilience in vertebrates is from specific areas of the brain from adult rodents or humans. In order to study resilience during development, we established a new paradigm to identify resilience in zebrafish larvae. Using this assay, we identified resilient and susceptible subsets of zebrafish larvae at 6 days post fertilization and performed gene expression analysis on whole larvae.
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Project description:<p>The Genomic Predictors of Combat Stress Vulnerability and Resilience Study was designed to probe the likely hereditary basis for risk or resilience to develop PTSD and other trauma spectrum disorders. The overall guiding hypothesis was that genomic variation gives rise to risk/susceptibility traits that, when actuated by traumatic environmental stimuli, such as combat, give rise to PTSD and other stress-related phenotypes.</p> <p>Two studies designed to identify risk and resilience factors for combat-induced, stress-related symptoms are being conducted by our group: The Marine Resiliency Study (MRS) is a prospective PTSD study with longitudinal follow-up (pre- and post-exposure to combat stress) of US Marines bound for deployment to Iraq or Afghanistan. Extensive phenotyping includes 3 domains: Psychosocial, Psychophysiologic, and Biophysiologic. The biological and physiological measures collected were chosen in part due to their potential to serve as intermediate phenotypes for stress-related disorders. A second, cross-sectional study involves a cohort of combat-exposed active duty or previously deployed service members (CAVC), including PTSD cases and controls with comparable psychosocial and clinical phenotypes.</p> <p>Little information is available about the factors that explain why some trauma survivors develop stress disorders and some do not. It is hoped that the insights gained from this approach will improve understanding of the genetic contributors to PTSD, and potentially provide novel diagnostic tests and therapeutic approaches to this currently enigmatic and difficult-to-manage condition.</p>
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Project description:Proteostasis is essential for survival and particularly important for highly specialized post mitotic cells like neurons. Transient reduction of protein synthesis by protein kinase R–like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. We employed PERK-deficient neuron and astrocyte monocultures to investigate the mechanisms underlying neuron-specific ER stress resilience in the absence of PERK.
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Project description:Transthyretin orchestrates vitamin B12-induced stress resilience
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Project description:Background: Chronic stress significantly contributes to mood- and anxiety disorders. Previous data suggest a correlative connection between vitamin B12 supplementation, depression, and stress resilience. However, the underlying mechanisms are still poorly understood. Methods: Using the chronic variable stress mouse model coupled with RNA-sequencing, we determined vitamin B12-induced transcriptional changes related to stress resilience. By viral-mediated gene transfer and in vivo epigenome editing, we reveal a functional pathway linking vitamin B12, DNA methylation, and depressive-like symptoms. Results: We identified Transthyretin (Ttr) as a sex-specific key target of vitamin B12 action in chronic stress. Accordingly, TTR expression was increased postmortem in the prefrontal cortex of male, but not female, depressed patients. Virally altered Ttr in the prefrontal cortex functionally contributed to stress- and depression-related behaviors, changes in dendritic spine morphology, and gene expression. In stressed mice, vitamin B12 reduced DNAme in the Ttr promoter region. Importantly, using in vivo epigenome editing to alter DNAme in the brains of living mice for the first time, we establish a direct causal link between DNAme on Ttr and stress-associated behaviors. Discussion: In summary, using state-of-the-art techniques, this study uncovers a mechanistic link between cobalamin supplementation, Ttr, and markers of chronic stress and depression, encouraging further studies into dietary interventions for mood disorders.
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Project description:We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and established a previously unknown role for the glial marker xCT in the homeostatic regulation of the ventral dentate gyrus (vDG) in stress resilience and antidepressant responses. We provide RNAseq roadmap for the stress-sensitive vDG and show that the transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27acet, to negatively regulate xCT expression. Reduced xCT was also observed in a genetic mouse model of inherent susceptibility to depression. Pharmacologically modulating histone acetylation with next-generation therapeutics, such as acetyl-N-cysteine (NAC) or acetyl-L-carnitine (LAC), rapidly increased xCT reduction and activated a network that included mGlu2 receptors to prime an enhanced glutamate homeostasis that promoted stress resilience and antidepressant-like responses. Moreover, pharmacological xCT blockage counteracted NAC prophylactic effects. Anatomical (vDG) and cell-type specific (GFAP+) virus-overexpression mimicked the effects of pharmacological treatments in increasing stress resilience. These findings establish xCT as critical regulator of the glutamate system in a network with mGlu2 receptors. These studies also point to a role of histone acetylation as mediator of stress resilience.
2017-10-11 | GSE103435 | GEO
Project description:Stress resilience involves numerous brain-wide transcriptional changes. Determining the organization and orchestration of these transcriptional events may reveal novel antidepressant targets, but this remains unexplored. Here, we characterize the resilient transcriptome with co-expression analysis and identify a single transcriptionally-active uniquely-resilient gene network. Zfp189, a previously unstudied zinc finger protein, is the top network key driver and its overexpression in prefrontal cortical (PFC) neurons preferentially activates this network, alters neuronal activity and promotes behavioral resilience. CREB, which binds Zfp189, is the top upstream regulator of this network. To probe CREB-Zfp189 interactions as a network regulatory mechanism, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB selectively to the Zfp189 promoter. This single molecular interaction in PFC neurons recapitulates the pro-resilient Zfp189-dependent downstream effects on gene network activity, electrophysiology and behavior. These findings reveal an essential role for Zfp189 and a CREB-Zfp189 regulatory axis in mediating a central transcriptional network of resilience.
2019-08-22 | GSE118317 | GEO