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Extensive overlap of the STAT6 and RXR cistromes in the active enhancer repertoire of human CD14+ monocyte-derived differentiating macrophages

ABSTRACT: Macrophages are able to differentiate into classically polarized (M1) or alternatively polarized (M2) states upon encountering pro-inflammatory cytokines such as interferon (IFN) g or anti-inflammatory cytokines such as interleukin (IL) -4/IL-13, respectively. Moreover, macrophages are known to regulate lipid metabolism via multiple members of the nuclear hormone receptor family, including the retinoid X receptors (RXR). It has been also documented that cytokines are able to modulate macrophage responses to lipid signals but the nature of these interactions and the underlying mechanisms of these processes especially at the level of the chromatinized genome are not well understood. Previous work from our laboratory suggested that STAT6 is a facilitator of nuclear receptor mediated transcriptional activity acting at the genome level. This prompted us to investigate genome-wide DNA binding events and the development of cistromes in human CD14+ monocyte-derived macrophages upon exposure to IL-4. We determined the impact of IL-4 on the PU.1, RXR and STAT6 cistromes within the active enhancer regions marked by H3K27-acetylation using chromatin immunoprecipitation followed by deep sequencing and integrated bioinformatics analyses. We found that about 2/3rd of the IL-4 induced STAT6 peaks co-localized with RXR peaks. These STAT6/RXR co-peaks differed at least in part from the non-overlapping RXR peaks regarding the most enriched de novo transcription factor binding motifs. Interestingly, RXR-binding was not regulated at the STAT6/RXR co-bound enhancers following IL-4 stimulation, but differential enhancer interactions were observed between the IL-4/STAT6 and RXR signaling pathways acting in a gene selective manner. Our results suggest that there is a novel, so far uncharacterized cistromic crosstalk between RXR and STAT6 that is likely to contribute to the formation of the active enhancer repertoire, transcriptome and differential signal-specific gene regulation of polarized macrophages.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100889 | GEO | 2017/07/07

REPOSITORIES: GEO

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Project description:Tumor-associated macrophages (TAM) represent an abundant cell population of the immune infiltrate in solid tumors and have been shown to orchestrate escape from immune surveillance. Macrophages display a very plastic phenotype which is recapitulated in vitro by classifying certain subsets according to exposure with defined, individual cytokines. The tumor-promoting M2 macrophages are polarized in vitro by differentiating human monocyte-derived macrophages with the T helper cell type 2 (Th2) response cytokines interleukin-4 and interleukin-13 or the immunosuppressive cytokine interleukin-10. Notably, only the latter macrophage subset undergoes apoptosis when treated with the colony stimulating factor 1 receptor (CSF1R) blocking antibody emactuzumab. However, under physiologic conditions the phenotype of TAM is shaped by a combination of cytokines. Hence, we evaluated if the addition of IL-10 to IL-4 or IL-13 differentiated macrophages is able to override IL-4/-13 mediated signaling and to restore susceptibility to emactuzumab. Though addition of IL-10 did not restore emactuzumab susceptibility, we surprisingly detected that only IL-4 differentiated macrophages sustained their specific marker expression while IL-10 skewed the IL-13 differentiated macrophage profile towards the IL-10 regulated phenotype. In-depth characterization by gene expression profiling revealed unique signatures of IL-4+IL-10 and IL-13+IL-10 differentiated macrophage subsets characterized by upregulation of the canonical NFÎºB signaling or Wnt/Î²-catenin signaling pathways, respectively. In silico-based analysis of a large cohort of cancer patients revealed distinct interleukin-4 or interleukin-13 overexpression patterns in a subset of patients with partial co-expression of IL-10 but almost absent IL-4/IL-13 co-expression. These patients may have less TAM depletion under therapy with CSF1R inhibitors. Five different macrophage subtypes were differentiated for six days with respect to different cytokines and transcriptomically profiled with three biological replicates derived from three different human, healthy volunteer donors

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Extensive overlap of the STAT6 and RXR cistromes in the active enhancer repertoire of human CD14+ monocyte-derived differentiating macrophages

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