Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes.
Comp. Struc. Biotech. J. 20, 5622-5638 (2022)
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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Typ der Hochschulschrift
Herausgeber
Schlagwörter
Glucocorticoid Receptor ; Inflammation ; Macrophages ; Ribosome Profiling ; Rna-seq ; Translational Regulation
Keywords plus
Sprache
englisch
Veröffentlichungsjahr
2022
Prepublished im Jahr
HGF-Berichtsjahr
2022
ISSN (print) / ISBN
2001-0370
e-ISSN
2001-0370
ISBN
Bandtitel
Konferenztitel
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Konferenzort
Konferenzband
Quellenangaben
Band: 20,
Heft: ,
Seiten: 5622-5638
Artikelnummer: ,
Supplement: ,
Reihe
Verlag
Research Network of Computational and Structural Biotechnology (RNCSB)
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Tag d. mündl. Prüfung
0000-00-00
Betreuer
Gutachter
Prüfer
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Veröffentlichungsdatum
0000-00-00
Anmeldedatum
0000-00-00
Anmelder/Inhaber
weitere Inhaber
Anmeldeland
Priorität
Begutachtungsstatus
Peer reviewed
POF Topic(s)
90000 - German Center for Diabetes Research
30201 - Metabolic Health
Forschungsfeld(er)
Helmholtz Diabetes Center
PSP-Element(e)
G-501900-227
G-502595-001
Förderungen
Horizon 2020
Else Kroner-Fresenius-Stiftung
Fondation Leducq
Deutsche Forschungsgemeinschaft
European Research Council
NHU
Copyright
Erfassungsdatum
2022-11-25