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Identification of potential target neuronal genes of class I histone deacetylase inhibitor treatment.

ABSTRACT: Class I histone deacetylase (HDAC) inhibitors are believed to have positive effects on neurite outgrowth, synaptic plasticity, and neurogenesis in adult brain. However, the downstream targets of class I HDAC inhibitor treatment in neurons are fully unclear. Although class I HDAC inhibitors are thought to broadly promote transcription of many neuronal genes through enhancement of histone acetylation, it is very interesting that the gene set might include as yet unidentified genes that are essential for neuronal survival and function. To identify novel target genes of class I HDAC inhibitor treatment, we screened transcripts of neuronal cultures with microarray using valproate acid.

ORGANISM(S): Mus musculus

PROVIDER: GSE90137 | GEO | 2016/11/23

SECONDARY ACCESSION(S): PRJNA354563

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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Identification of potential target neuronal genes of class I histone deacetylase inhibitor treatment.

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