The transcription factor EGR2 is the molecular linchpin connecting STAT6 activation to the late, stable epigenomic program of alternative macrophage polarization

Bence Daniel, Zsolt Czimmerer, Laszlo Halasz, Pal Boto, Zsuzsanna Kolostyak, Szilard Poliska, Wilhelm K. Berger, Petros Tzerpos, Gergely Nagy, Attila Horvath, György Hajas, Timea Cseh, Aniko Nagy, Sascha Sauer, Jean Francois-Deleuze, Istvan Szatmari, Attila Bacsi, Laszlo Nagy

Research output: Contribution to journalArticlepeer-review

Abstract

Macrophages polarize into functionally distinct subtypes while responding to microenvironmental cues. The identity of proximal transcription factors (TFs) downstream from the polarization signals are known, but their activity is typically transient, failing to explain the long-Term, stable epigenomic programs developed. Here, we mapped the early and late epigenomic changes of interleukin-4 (IL-4)-induced alternative macrophage polarization. We identified the TF, early growth response 2 (EGR2), bridging the early transient and late stable gene expression program of polarization. EGR2 is a direct target of IL-4-Activated STAT6, having broad action indispensable for 77% of the induced gene signature of alternative polarization, including its autoregulation and a robust, downstream TF cascade involving PPARG. Mechanistically, EGR2 binding results in chromatin opening and the recruitment of chromatin remodelers and RNA polymerase II. Egr2 induction is evolutionarily conserved during alternative polarization of mouse and human macrophages. In the context of tissue resident macrophages, Egr2 expression is most prominent in the lung of a variety of species. Thus, EGR2 is an example of an essential and evolutionarily conserved broad acting factor, linking transient polarization signals to stable epigenomic and transcriptional changes in macrophages.

Original languageEnglish (US)
Pages (from-to)1474-1492
Number of pages19
JournalGenes and Development
Volume34
Issue number21-22
DOIs
StatePublished - Nov 1 2020

Keywords

  • EGR2
  • Epigenomic regulation
  • IL-4
  • Macrophage polarization
  • Transcription factor network

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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