Fig. 1
The 3p21.31 severe COVID-19 risk locus harbours a 3D chromatin hub that controls monocyte-macrophage chemokine receptor expression. a FUMA regional plot of the 3p21.31 locus highlighting all variants in high linkage-disequilibrium (r2>0.8, P<0.05) with independent significant (P<5e−8) GWAS SNPs. Bar graph denotes SNP distribution. b Number of COVID-19-associated SNPs overlapping with H3K27Ac+ regions in the indicated cell types. c UCSC genome browser view of H3K27Ac ChIP-Seq tracks for the indicated cell or tissue types (fibro. = fibroblast, epith. = epithelial, Mph = macrophage, mem. B = memory B cell). Genes and FUMA SNPs are shown above, yellow shading indicates location monocyte/macrophage-specific active chromatin regions (‘ACR1-3′). d Normalized gene expression levels (transcripts per million; TPM) of 3p21.31 candidate genes across various immune cell subsets from peripheral blood (DICE and HaemoSphere databases) and in vitro transdifferentiated induced macrophages (iMacs [10]). e Circos plots showing significant chromatin interactions with the CCR1 promoter (green dashed line) in LPS stimulated macrophages or CD8+ T cells as measured by promoter-capture Hi-C (freq.: frequency). ACRs are indicated in orange. f Schematic indicating active chromatin hub formation involving the ACRs (enhancer; Enh.), CTCF binding sites and indicated CCR genes in monocytes/macrophages. g Experimental scheme depicting C/EBPα-driven transdifferentiation of B cells carrying CTCF-mAID alleles into iMacs. Exposure to auxin induces rapid degradation of CTCF-mAID [10]. h Hi-C interaction matrices (5 kb resolution, smoothened) for iMacs before (left) and after (right) auxin-inducible CTCF degradation, resulting in weaker interactions (indicated by numbers) between CCR genes and/or ACR1 (colour code as in panel f). CTCF ChIP-Seq peaks in iMacs are indicated below. i Gene expression changes of indicated genes in iMacs after CTCF degradation