Extensive overlap of the STAT6 and RXR cistromes in the active enhancer repertoire of human CD14+ monocyte-derived differentiating macrophages. Homo sapiens isolate:hMQL

Macrophages are able to differentiate into classically polarized (M1) or alternatively polarized (M2) states upon encountering pro-inflammatory cytokines such as interferon (IFN) γ or anti-inflammatory cytokines such as interleukin (IL) -4/IL-13, respectively. Moreover, macrophages are known to regulate lipid metabolism via several members of the nuclear hormone receptor superfamily, including retinoid X receptors (RXRs). It has been documented that cytokines are able to modulate macrophage responses to lipid signals but the underlying mechanisms of these events at the genomic level are not well understood. Previous work suggested that STAT6 is a facilitator of nuclear receptor mediated events acting likely at the genome level, which prompted us to investigate genome-wide DNA binding events (cistromes) in human CD14+ monocyte-derived macrophages in the presence and absence of 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 bioinformatic analyses. We found that about 2/3rd of the IL-4-induced STAT6 peaks co-localized with RXR peaks. These binding sites had a distinct motif enrichment profile as compared to the non-overlapping RXR peaks. Interestingly, short-term IL-4 exposure did not change RXR-binding on the STAT6/RXR co-bound enhancers. The functional consequences of the uncovered cistromic interaction between IL-4/STAT6 and RXR signaling pathways include additive and synergistic gene expression events.