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Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes

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Item Type:Article
Title:Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes
Creators Name:Ansari, S.A., Dantoft, W., Ruiz-Orera, J., Syed, A.P., Blachut, S., van Heesch, S., Hübner, N. and Uhlenhaut, N.H.
Abstract:Glucocorticoids such as dexamethasone (Dex) are widely used to treat both acute and chronic inflammatory conditions. They regulate immune responses by dampening cell-mediated immunity in a glucocorticoid receptor (GR)-dependent manner, by suppressing the expression of pro-inflammatory cytokines and chemokines and by stimulating the expression of anti-inflammatory mediators. Despite its evident clinical benefit, the mechanistic underpinnings of the gene regulatory networks transcriptionally controlled by GR in a context-specific manner remain mysterious. Next generation sequencing methods such mRNA sequencing (RNA-seq) and Ribosome profiling (ribo-seq) provide tools to investigate the transcriptional and post-transcriptional mechanisms that govern gene expression. Here, we integrate matched RNA-seq data with ribo-seq data from human acute monocytic leukemia (THP-1) cells treated with the TLR4 ligand lipopolysaccharide (LPS) and with Dex, to investigate the global transcriptional and translational regulation (translational efficiency, ΔTE) of Dex-responsive genes. We find that the expression of most of the Dex-responsive genes are regulated at both the transcriptional and the post-transcriptional level, with the transcriptional changes intensified on the translational level. Overrepresentation pathway analysis combined with STRING protein network analysis and manual functional exploration, identified these genes to encode immune effectors and immunomodulators that contribute to macrophage-mediated immunity and to the maintenance of macrophage-mediated immune homeostasis. Further research into the translational regulatory network underlying the GR anti-inflammatory response could pave the way for the development of novel immunomodulatory therapeutic regimens with fewer undesirable side effects.
Keywords:Glucocorticoid Receptor, Macrophages, Inflammation, Ribosome Profiling, RNA-Seq, Translational Regulation
Source:Computational and Structural Biotechnology Journal
ISSN:2001-0370
Publisher:Elsevier
Volume:20
Page Range:5622-5638
Date:3 October 2022
Official Publication:https://doi.org/10.1016/j.csbj.2022.09.042
PubMed:View item in PubMed

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