Negative elongation factor complex enables macrophage inflammatory responses by controlling anti-inflammatory gene expression. Academic Article uri icon

Overview

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.

publication date

  • May 8, 2020

Research

keywords

  • Anti-Inflammatory Agents
  • Gene Expression Regulation
  • Inflammation
  • Macrophages
  • Transcription Factors

Identity

PubMed Central ID

  • PMC7210294

Scopus Document Identifier

  • 85084721205

Digital Object Identifier (DOI)

  • 10.1038/nature10730

PubMed ID

  • 32385332

Additional Document Info

volume

  • 11

issue

  • 1