The transcription factor EGR2 is the molecular linchpin connecting STAT6 activation to the late, stable epigenomic program of alternative macrophage polarization.
The transcription factor EGR2 is the molecular linchpin connecting STAT6 activation to the late, stable epigenomic program of alternative macrophage polarization.
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DOI：
10.1101/gad.343038.120
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发表时间：
2020-11-01
影响因子：
10.5
通讯作者：
Nagy L
中科院分区：
文献类型：
--
作者：
Daniel B;Czimmerer Z;Halasz L;Boto P;Kolostyak Z;Poliska S;Berger WK;Tzerpos P;Nagy G;Horvath A;Hajas G;Cseh T;Nagy A;Sauer S;Francois-Deleuze J;Szatmari I;Bacsi A;Nagy L
在这项研究中，Daniel等人研究了巨噬细胞极化的一般机制，特别是选择性极化的机制。利用无偏的表观基因组学、分子生物学和遗传GOF和LOF方法，作者表明锌指转录因子EGR2是巨噬细胞中一个重要的、进化上保守的广谱作用因子，将瞬态极化信号与稳定的表观基因组和转录变化联系起来。巨噬细胞在响应微环境信号时分化成功能不同的亚型。来自极化信号下游的近端转录因子（TFs）的身份是已知的，但它们的活性通常是短暂的，无法解释长期稳定的表观基因组程序。在这里，我们绘制了白细胞介素-4 （IL-4）诱导的巨噬细胞选择性极化的早期和晚期表观基因组变化。我们发现了TF，早期生长反应2 (EGR2)，连接早期瞬态和晚期稳定的极化基因表达程序。EGR2是il -4激活的STAT6的直接靶标，对77%的选择性极化诱导基因特征具有广泛的作用，包括其自动调节和涉及PPARG的强大的下游TF级联。从机制上讲，EGR2结合导致染色质打开，染色质重塑子和RNA聚合酶II的募集。在小鼠和人巨噬细胞的交替极化过程中，Egr2诱导是进化保守的。在组织常驻巨噬细胞中，Egr2的表达在多种物种的肺中最为突出。因此，EGR2是一个重要的、进化上保守的广泛作用因子的例子，它将巨噬细胞的瞬态极化信号与稳定的表观基因组和转录变化联系起来。
In this study, Daniel et al. examined the mechanisms of macrophage polarization in general and alternative polarization in particular. Using unbiased epigenomic, molecular biology, and genetic GOF and LOF approaches, the authors show that the zinc finger transcription factor EGR2 acts as an essential and evolutionarily conserved broad-acting factor, linking transient polarization signals to stable epigenomic and transcriptional changes in macrophages. 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.
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影响因子：
3.7
作者：
Jablonski KA;Amici SA;Webb LM;Ruiz-Rosado Jde D;Popovich PG;Partida-Sanchez S;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
DOI：
10.1038/nrm3949
发表时间：
2015-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Heinz S;Romanoski CE;Benner C;Glass CK
通讯作者：
Glass CK
影响因子：
64.5
作者：
Lavin Y;Winter D;Blecher-Gonen R;David E;Keren-Shaul H;Merad M;Jung S;Amit I
通讯作者：
Amit I
影响因子：
10.5
作者：
Daniel B;Nagy G;Hah N;Horvath A;Czimmerer Z;Poliska S;Gyuris T;Keirsse J;Gysemans C;Van Ginderachter JA;Balint BL;Evans RM;Barta E;Nagy L
通讯作者：
Nagy L