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Impact of the vitamin B12 on the transcriptional regulation of the Mycobacterium tuberculosis Complex

ABSTRACT: The transcriptome in response to vitamin B12 was interrogated in three M. tuberculosis Complex species: M. tuberculosis H37Rv, M. tuberculosis GC1237, and M. bovis AF2122/97. Examination of the core B12 transcriptome resulted in a robust differential regulation of 7 genes in the three species analysed

ORGANISM(S): Mycobacterium tuberculosis Mycobacterium tuberculosis variant bovis

PROVIDER: GSE232691 | GEO | 2023/12/22

REPOSITORIES: GEO

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Transcriptomic changes associated with growth of Mycobacterium tuberculosis H37Rv wild-type strain and ∆prpR mutant in mineral medium supplemented with cholesterol as the sole carbon source or standard medium supplemented with vitamin B12.

Project description:RNA-Seq results accompanying submission of a manuscript: "Cholesterol-dependent transcriptome remodeling reveals new insight into the contribution of cholesterol to Mycobacterium tuberculosis pathogenesis" describing the role of cholesterol and vitamin B12 in shaping the transcriptome of the Mycobacterium tuberculosis H37Rv and M. tuberculosis ∆prpR - propionate regulator (PrpR) mutant. Next generation sequencing results are provided in three independent biological replicates for each strain growing in three different media - minimal medium with glycerol or cholesterol as the sole carbon source and standard 7H9/10% OADC medium. The influence of vitamin B12 on M. tuberculosis transcriptome was analysed on 7H9/10% OADC medium supplemented with B12. The study allowed us to re-establish the list of genes potentially involved in cholesterol metabolism. We further proposed a novel regulatory function of vitamin B12 and PrpR, a propionate regulator, in coordinated cholesterol breakdown metabolite dissipation and virulent phenotype induction. Finally, we demonstrated that a key role of cholesterol in Mtb metabolism is not only providing carbon and energy but also inducing a transcriptome remodeling program that helps in developing tolerance to the unfavorable host cell environment.

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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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