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

Li Yu, Bin Zhang, Dinesh Deochand, Maria A. Sacta, Maddalena Coppo, Yingli Shang, Ziyi Guo, Xiaomin Zeng, David A. Rollins, Bowranigan Tharmalingam, Rong Li, Yurii Chinenov, Inez Rogatsky () and Xiaoyu Hu ()
Additional contact information
Li Yu: Tsinghua University
Bin Zhang: Tsinghua University
Dinesh Deochand: Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center
Maria A. Sacta: Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center
Maddalena Coppo: Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center
Yingli Shang: Shandong Agricultural University
Ziyi Guo: Tsinghua University
Xiaomin Zeng: Tsinghua University
David A. Rollins: Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center
Bowranigan Tharmalingam: Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center
Rong Li: The George Washington University
Yurii Chinenov: Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center
Inez Rogatsky: Hospital for Special Surgery Research Institute, The David Rosensweig Genomics Center
Xiaoyu Hu: Tsinghua University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-16209-5

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