Negative elongation factor complex enables macrophage inflammatory responses by controlling anti-inflammatory gene expression.

Animals Anti-Inflammatory Agents / metabolism Chromatin / metabolism Gene Expression Regulation Inflammation / genetics Interleukin-10 / metabolism Macrophage Activation / genetics Macrophages / metabolism Mice Nucleotide Motifs / genetics Promoter Regions, Genetic RNA Polymerase II / metabolism Transcription Factors / metabolism Transcription Initiation Site Transcription, Genetic Transcriptional Activation / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
08 05 2020
Historique:
received: 28 04 2019
accepted: 21 04 2020
entrez: 10 5 2020
pubmed: 10 5 2020
medline: 6 8 2020
Statut: epublish

Résumé

Studies on macrophage gene expression have historically focused on events leading to RNA polymerase II recruitment and transcription initiation, whereas the contribution of post-initiation steps to macrophage activation remains poorly understood. Here, we report that widespread promoter-proximal RNA polymerase II pausing in resting macrophages is marked by co-localization of the negative elongation factor (NELF) complex and facilitated by PU.1. Upon inflammatory stimulation, over 60% of activated transcriptome is regulated by polymerase pause-release and a transient genome-wide NELF dissociation from chromatin, unexpectedly, independent of CDK9, a presumed NELF kinase. Genetic disruption of NELF in macrophages enhanced transcription of AP-1-encoding Fos and Jun and, consequently, AP-1 targets including Il10. Augmented expression of IL-10, a critical anti-inflammatory cytokine, in turn, attenuated production of pro-inflammatory mediators and, ultimately, macrophage-mediated inflammation in vivo. Together, these findings establish a previously unappreciated role of NELF in constraining transcription of inflammation inhibitors thereby enabling inflammatory macrophage activation.

Identifiants

DOI: 10.1038/s41467-020-16209-5 PMID: 32385332 PMC: PMC7210294
pubmed: 32385332
doi: 10.1038/s41467-020-16209-5
pii: 10.1038/s41467-020-16209-5
pmc: PMC7210294
doi:

Substances chimiques

Anti-Inflammatory Agents 0
Chromatin 0
Transcription Factors 0
negative elongation factor 0
Interleukin-10 130068-27-8
RNA Polymerase II EC 2.7.7.-

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

2286

Subventions

Organisme : NIAID NIH HHS
ID : R01 AI148129
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099087
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA220578
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK115219
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007739
Pays : United States
Organisme : NIAMS NIH HHS
ID : T32 AR007281
Pays : United States

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Auteurs

Li Yu (L)

Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.
Tsinghua-Peking Centre for Life Sciences, Tsinghua University, Beijing, China.
Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing, China.

Bin Zhang (B)

Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.
Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing, China.
ORCID: 0000-0001-6232-6768

Dinesh Deochand (D)

Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, USA.
ORCID: 0000-0002-7395-9250

Maria A Sacta (MA)

Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, USA.
Weill Cornell/Sloan Kettering/Rockefeller Tri-Institutional MD-PhD Program, 1300 York Avenue, New York, NY, USA.

Maddalena Coppo (M)

Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, USA.

Yingli Shang (Y)

College of Veterinary Medicine, Shandong Agricultural University, Taian, China.

Ziyi Guo (Z)

Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.
Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing, China.

Xiaomin Zeng (X)

Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.
Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing, China.

David A Rollins (DA)

Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, USA.
Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, NY, USA.

Bowranigan Tharmalingam (B)

Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, USA.

Rong Li (R)

Department of Biochemistry & Molecular Medicine School of Medicine & Health Sciences, The George Washington University, 2300 I Street NW, Washington, DC, USA.

Yurii Chinenov (Y)

Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, USA.

Inez Rogatsky (I)

Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY, USA. rogatskyi@hss.edu.
Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, NY, USA. rogatskyi@hss.edu.
ORCID: 0000-0003-3514-5077

Xiaoyu Hu (X)

Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China. xiaoyuhu@tsinghua.edu.cn.
Tsinghua-Peking Centre for Life Sciences, Tsinghua University, Beijing, China. xiaoyuhu@tsinghua.edu.cn.
Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing, China. xiaoyuhu@tsinghua.edu.cn.
ORCID: 0000-0002-4289-6998

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Negative elongation factor complex enables...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-inflammatoires › Negative elongation factor complex enables...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Structures de chromosome › Chromatine › Negative elongation factor complex enables...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Negative elongation factor complex enables...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Negative elongation factor complex enables...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interleukines › Interleukine-10 › Negative elongation factor complex enables...
questionsmedicales.fr › Phénomènes du système immunitaire › Cytotoxicité immunologique › Activation des macrophages › Negative elongation factor complex enables...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Phagocytes › Macrophages › Negative elongation factor complex enables...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Negative elongation factor complex enables...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Conformation d'acide nucléique › Motifs nucléotidiques › Negative elongation factor complex enables...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Régions promotrices (génétique) › Negative elongation factor complex enables...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Nucleotidyltransferases › RNA nucleotidyltransferases › DNA-directed RNA polymerases › RNA polymerase II › Negative elongation factor complex enables...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Negative elongation factor complex enables...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Site d'initiation de la transcription › Negative elongation factor complex enables...
questionsmedicales.fr › Phénomènes génétiques › Expression des gènes › Transcription génétique › Negative elongation factor complex enables...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Activation de la transcription › Negative elongation factor complex enables...