Fig. 4. ETS2 directs macrophage responses through transcriptional and metabolic effects.

a, Genes co-expressed with ETS2 across 67 monocyte/macrophage activation conditions. The dotted lines denote FDR-adjusted P < 0.05. b, The effect of ETS2 disruption on glucose metabolism. The colour denotes median log₂-transformed fold change in label incorporation from ¹³C-glucose in ETS2-edited versus unedited cells. The bold black border denotes P < 0.05 (Wilcoxon matched-pairs, two-sided). n = 6. Sec., secreted. c, fGSEA analysis of differentially expressed genes between ETS2-edited and unedited macrophages that were treated with roxadustat or vehicle. Results shown for pathways downregulated by ETS2 disruption. d, Enrichment heat maps of macrophage ETS2 CUT&RUN peaks (IDR cut-off 0.01, n = 2) in 4 kb peak-centred regions from ATAC–seq (accessible chromatin), H3K4me3 ChIP–seq (active promoters) and H3K27ac ChIP–seq (active regulatory elements). e, Functional annotations of ETS2-binding sites (using gene coordinates and TPP macrophage H3K27ac ChIP–seq data). f, ETS2 motif enrichment in CUT&RUN peaks (hypergeometric P value, two-sided). g, ETS2 binding, chromatin accessibility (ATAC–seq) and regulatory activity (H3K27ac) at selected loci. h, Intersections between genes with ETS2 peaks in their core promoters or cis-regulatory elements and genes upregulated (Up) or downregulated (Dn) after ETS2 editing (KO) or overexpression (OE). The vertical bars denote the size of overlap for lists indicated by connected dots in the bottom panel. The horizontal bars denote the percentage of gene list within intersections. i, ETS2 binding, PU.1 binding, chromatin accessibility and enhancer activity at chr21q22. Predicted ETS2-binding sites (red) and PU.1-binding sites (purple) shown below. The dashed line is positioned at rs2836882.

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