TY - JOUR
T1 - The transcription factor EGR2 is the molecular linchpin connecting STAT6 activation to the late, stable epigenomic program of alternative macrophage polarization
AU - Daniel, Bence
AU - Czimmerer, Zsolt
AU - Halasz, Laszlo
AU - Boto, Pal
AU - Kolostyak, Zsuzsanna
AU - Poliska, Szilard
AU - Berger, Wilhelm K.
AU - Tzerpos, Petros
AU - Nagy, Gergely
AU - Horvath, Attila
AU - Hajas, György
AU - Cseh, Timea
AU - Nagy, Aniko
AU - Sauer, Sascha
AU - Francois-Deleuze, Jean
AU - Szatmari, Istvan
AU - Bacsi, Attila
AU - Nagy, Laszlo
N1 - Publisher Copyright:
© 2020 Cold Spring Harbor Laboratory Press. All rights reserved.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
KW - EGR2
KW - Epigenomic regulation
KW - IL-4
KW - Macrophage polarization
KW - Transcription factor network
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U2 - 10.1101/gad.343038.120
DO - 10.1101/gad.343038.120
M3 - Article
C2 - 33060136
AN - SCOPUS:85095444133
SN - 0890-9369
VL - 34
SP - 1474
EP - 1492
JO - Genes and Development
JF - Genes and Development
IS - 21-22
ER -