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Transthyretin (Ttr/TTR) emerged as a key sex-specific target, with B12 lowering Ttr promoter DNAme and establishing causality between DNA methylation and Ttr-associated 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question does the study address about vitamin B12 and chronic stress?","Question",{"text":63,"@type":64},"It investigates how vitamin B12 supplementation mediates stress resilience and improves depression-related markers at a molecular level, which had remained poorly understood.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How did the researchers model chronic stress and examine vitamin B12 effects?",{"text":68,"@type":64},"They used the chronic variable stress (CVS) mouse model, combined with RNA sequencing, viral-mediated gene transfer, and in vivo epigenome editing to measure transcriptional, epigenetic, and behavioral changes.",{"name":70,"@type":61,"acceptedAnswer":71},"What role does transthyretin (Ttr/TTR) play in the findings?",{"text":72,"@type":64},"Ttr was identified as a key sex-specific target of vitamin B12 in chronic stress, with TTR expression increased after death in male but not female patients with depression, and virally altered Ttr affecting stress/depression-related behaviors and gene expression.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},405449,1790767419,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & 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Author Manuscr ipt Author Manuscript  \n\n| | HHS Public Access\u003Cbr>Author manuscript\u003Cbr>Biol Psychiatry. Author manuscript; available in PMC 2026 January 01. |\n| --- | --- |\n\nPublished in final edited form as:  \nBiol Psychiatry. 2025 January 01; 97(1): 54–63. doi:10.1016/j.biopsych.2024.07.009 .  \nTransthyretin Orchestrates Vitamin B12–Induced Stress Resilience  \nGregor Stein,  \nInstitute for Biochemistry and Biophysics, Friedrich Schiller University, Jena, Germany  \nJanine S. Aly,  \nInstitute of Human Genetics, Jena University Hospital, Jena, Germany  \nAnnamaria Manzolillo,  \nInstitute of Human Genetics, Jena University Hospital, Jena, Germany  \nLisa Lange,  \nInstitute for Biochemistry and Biophysics, Friedrich Schiller University, Jena, Germany  \nKonstantin Riege,  \nComputational Biology Group, Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany Iqra Hussain,  \nInstitute for Biochemistry and Biophysics, Friedrich Schiller University, Jena, Germany  \nElisabeth A. Heller,  \nDepartment of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania  \nSusana Cubillos,  \nInstitute for Biochemistry and Biophysics, Friedrich Schiller University, Jena, Germany  \nThomas Ernst,  \nClinic for Internal Medicine II, Jena University Hospital, Jena, Germany  \nChristian A. Hübner,  \nInstitute of Human Genetics, Jena University Hospital, Jena, Germany  \nGustavo Turecki,  \nDouglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Québec, Canada  \nSteve Hoffmann,  \nComputational Biology Group, Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany  \nOlivia Engmann  \nThis is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)). Address correspondence to Olivia Engmann, Ph.D., at olivia.engmann@uni-jena.de.  \nThe authors report no biomedical financial interests or potential conflicts of interest.  \nA previous version of this article was published as a preprint on bioRxiv: [https://www.biorxiv.org/content/](https://www.biorxiv.org/content/)[ ](https://www.biorxiv.org/content/)[10.1101/2024.02.07.578164v1.full](10.1101/2024.02.07.578164v1.full.)[.](10.1101/2024.02.07.578164v1.full.)  \nSupplementary material cited in this article is available online at [https://doi.org/10.1016/j.biopsych.2024.07.009](https://doi.org/10.1016/j.biopsych.2024.07.009) .  \nAuthor Manuscr ipt Author Manuscr ipt Author Manuscr ipt Author Manuscript  \nStein et al. Page 2  \nInstitute for Biochemistry and Biophysics, Friedrich Schiller University, Jena, Germany Institute of Human Genetics, Jena University Hospital, Jena, Germany  \nAbstract  \nBACKGROUND: Chronic stress significantly contributes to mood and anxiety disorders.  \nPrevious data suggest a correlative connection between vitamin B12 supplementation, depression, and stress resilience. However, the underlying mechanisms are still poorly understood.  \nMETHODS: Using the chronic variable stress mouse model coupled with RNA sequencing, we identified vitamin B12–induced transcriptional changes related to stress resilience. Using viral-mediated gene transfer and in vivo epigenome editing, we revealed a functional pathway linking vitamin B12, DNA methylation (DNAme), and depression-like symptoms.  \nRESULTS: We identified Ttr (transthyretin) as a key sex-specific target of vitamin B12 in chronic stress. Accordingly, TTR expression was increased postmortem in the prefrontal cortex of male but not female patients with depression. Virally altered Ttrin 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.  \nImportantly, using in vivo epigenome editing to alter DNAme in the brains of living mice for the first tim","cbCaidRVZPWR9G0R","https://ap.wps.com/l/cbCaidRVZPWR9G0R","pdf",1727883,21,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusions","[{\"question\":\"What question does the study address about vitamin B12 and chronic stress?\",\"answer\":\"It investigates how vitamin B12 supplementation mediates stress resilience and improves depression-related markers at a molecular level, which had remained poorly understood.\"},{\"question\":\"How did the researchers model chronic stress and examine vitamin B12 effects?\",\"answer\":\"They used the chronic variable stress (CVS) mouse model, combined with RNA sequencing, viral-mediated gene transfer, and in vivo epigenome editing to measure transcriptional, epigenetic, and behavioral changes.\"},{\"question\":\"What role does transthyretin (Ttr/TTR) play in the findings?\",\"answer\":\"Ttr was identified as a key sex-specific target of vitamin B12 in chronic stress, with TTR expression increased after death in male but not female patients with depression, and virally altered Ttr affecting stress/depression-related behaviors and gene expression.\"}]","Transthyretin Orchestrates Vitamin B12–Induced Stress Resilience | PDF",1790560141,53]