Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes
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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-01-01
|
| Series: | Computational and Structural Biotechnology Journal |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022004470 |
| _version_ | 1797978176822968320 |
|---|---|
| author | Suhail A. Ansari Widad Dantoft Jorge Ruiz-Orera Afzal P. Syed Susanne Blachut Sebastiaan van Heesch Norbert Hübner Nina Henriette Uhlenhaut |
| author_facet | Suhail A. Ansari Widad Dantoft Jorge Ruiz-Orera Afzal P. Syed Susanne Blachut Sebastiaan van Heesch Norbert Hübner Nina Henriette Uhlenhaut |
| author_sort | Suhail A. Ansari |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T05:18:49Z |
| format | Article |
| id | doaj.art-c56c0bed9fc4420d97347ba2a7faae0a |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:18:49Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-c56c0bed9fc4420d97347ba2a7faae0a2022-12-24T04:54:40ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-012056225638Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classesSuhail A. Ansari0Widad Dantoft1Jorge Ruiz-Orera2Afzal P. Syed3Susanne Blachut4Sebastiaan van Heesch5Norbert Hübner6Nina Henriette Uhlenhaut7Institute for Diabetes and Endocrinology (IDE), Helmholtz Center Munich (HMGU) and German Center for Diabetes Research (DZD), Neuherberg, GermanyInstitute for Diabetes and Endocrinology (IDE), Helmholtz Center Munich (HMGU) and German Center for Diabetes Research (DZD), Neuherberg, GermanyCardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, GermanyInstitute for Diabetes and Endocrinology (IDE), Helmholtz Center Munich (HMGU) and German Center for Diabetes Research (DZD), Neuherberg, GermanyCardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, GermanyPrincess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The NetherlandsCardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; Charite-Universitätsmedizin Berlin, Berlin, GermanyInstitute for Diabetes and Endocrinology (IDE), Helmholtz Center Munich (HMGU) and German Center for Diabetes Research (DZD), Neuherberg, Germany; Metabolic Programming, School of Life Sciences Weihenstephan, ZIEL – Institute for Food and Health, Technical University of Munich (TUM), Freising, Germany; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2001037022004470Glucocorticoid receptorMacrophagesInflammationRibosome profilingRNA-seqTranslational regulation |
| spellingShingle | Suhail A. Ansari Widad Dantoft Jorge Ruiz-Orera Afzal P. Syed Susanne Blachut Sebastiaan van Heesch Norbert Hübner Nina Henriette Uhlenhaut Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes Computational and Structural Biotechnology Journal Glucocorticoid receptor Macrophages Inflammation Ribosome profiling RNA-seq Translational regulation |
| title | Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes |
| title_full | Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes |
| title_fullStr | Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes |
| title_full_unstemmed | Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes |
| title_short | Integrative analysis of macrophage ribo-Seq and RNA-Seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes |
| title_sort | integrative analysis of macrophage ribo seq and rna seq data define glucocorticoid receptor regulated inflammatory response genes into distinct regulatory classes |
| topic | Glucocorticoid receptor Macrophages Inflammation Ribosome profiling RNA-seq Translational regulation |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022004470 |
| work_keys_str_mv | AT suhailaansari integrativeanalysisofmacrophageriboseqandrnaseqdatadefineglucocorticoidreceptorregulatedinflammatoryresponsegenesintodistinctregulatoryclasses AT widaddantoft integrativeanalysisofmacrophageriboseqandrnaseqdatadefineglucocorticoidreceptorregulatedinflammatoryresponsegenesintodistinctregulatoryclasses AT jorgeruizorera integrativeanalysisofmacrophageriboseqandrnaseqdatadefineglucocorticoidreceptorregulatedinflammatoryresponsegenesintodistinctregulatoryclasses AT afzalpsyed integrativeanalysisofmacrophageriboseqandrnaseqdatadefineglucocorticoidreceptorregulatedinflammatoryresponsegenesintodistinctregulatoryclasses AT susanneblachut integrativeanalysisofmacrophageriboseqandrnaseqdatadefineglucocorticoidreceptorregulatedinflammatoryresponsegenesintodistinctregulatoryclasses AT sebastiaanvanheesch integrativeanalysisofmacrophageriboseqandrnaseqdatadefineglucocorticoidreceptorregulatedinflammatoryresponsegenesintodistinctregulatoryclasses AT norberthubner integrativeanalysisofmacrophageriboseqandrnaseqdatadefineglucocorticoidreceptorregulatedinflammatoryresponsegenesintodistinctregulatoryclasses AT ninahenrietteuhlenhaut integrativeanalysisofmacrophageriboseqandrnaseqdatadefineglucocorticoidreceptorregulatedinflammatoryresponsegenesintodistinctregulatoryclasses |