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Characterize compounds that affect V(D)J recombination and chromsomal translocation using MP-HTGTS

ABSTRACT: V(D)J recombination represents a vital mechanism responsible for generating antibodies and T-cell receptors (TCR). This intricate process encompasses various stages, such as chromatin looping, RAG1/2 incision, end processing, and ligation. In our study, we conducted extensive screening using a diverse array of drugs from the FDA-approved list. Our primary objective was to gain insights into the impact of these drugs on V(D)J recombination and to elucidate potential side effects associated with their use. Notably, among the drugs examined, HDAC inhibitors stood out as they appeared to modulate V(D)J recombination initiation by potentially regulating upstream events. This investigation contributes valuable information to our understanding of how pharmaceutical agents may influence the intricate process of V(D)J recombination and highlights the distinctive role played by HDAC inhibitors in this context.

ORGANISM(S): Mus musculus

PROVIDER: GSE242857 | GEO | 2023/12/30

REPOSITORIES: GEO

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Project description:Sensing of microbial products by innate immune cells skew their transcriptional program to optimize anti-microbial defences. Chromatin remodeling by histone deacetylases (HDACs) plays a fundamental role in tailoring gene expression. HDAC inhibitors are among the most promising anti-cancer drugs and possess intrinsic anti-inflammatory properties. Yet, the influence of HDAC inhibition on innate immune responses to microbial infection is unknown. Here we show that HDAC inhibitors repress the expression of less than 10% of the genes expressed at baseline in BM-derived macrophages. In sharp contrast, HDAC inhibitors strongly interfere with transcriptome remodeling induced by LPS and Pam3CSK4, affecting the expression of 30-70% of genes modulated by microbial stimuli. Strikingly, HDAC inhibitors target the expression of numerous genes involved in anti-microbial host defences, encoding for microbial sensors, cytokines, chemokines, growth factors and their receptors, adhesion and signaling molecules, and molecules involved in antigen processing and presentation. At the molecular level, HDAC inhibitors do not impair mitogen-activated protein kinase, NF-kB, interferon-related factor signal and STAT1 transduction pathways, but inhibit NF-kB p65 recruitment to the promoter region of HDAC inhibitor-sensitive genes. HDAC inhibitors also inhibit the response of mouse and human DCs, splenocytes and whole blood to a broad range of microbial products and microorganisms. In agreement with these in vitro findings, HDAC inhibitors increase bacterial burden and sensitize mice to sub-lethal infection with Klebsiella pneumoniae and Candida albicans. Conversely, HDAC inhibitors confer protection in models of Pam3CSK4-induced fulminant toxic shock and severe sepsis following cecal ligation and puncture. Overall, these data substantiate the concept of immunomodulation by HDAC inhibitors, and suggest that these drugs could represent efficacious adjunctive therapy of severe sepsis. Mus musculus cells were grown in presence of LPS or LPS + TSA and pam or pam + TSA and hybrydised against a cRNA pool UMRR (from Mus musculus cells).

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Characterize compounds that affect V(D)J recombination and chromsomal translocation using MP-HTGTS

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