Enhancer Connectome Nominates Target Genes of Inherited Risk Variants from Inflammatory Skin Disorders Mark Y. Jeng, Maxwell R. Mumbach, Jeffrey M. Granja,

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Presentation transcript:

Enhancer Connectome Nominates Target Genes of Inherited Risk Variants from Inflammatory Skin Disorders Mark Y. Jeng, Maxwell R. Mumbach, Jeffrey M. Granja, Ansuman T. Satpathy, Howard Y. Chang, Anne Lynn S. Chang Journal of Investigative Dermatology Volume 139, Issue 3, Pages 605-614 (March 2019) DOI: 10.1016/j.jid.2018.09.011 Copyright © 2018 The Authors Terms and Conditions

Figure 1 H3K27ac HiChIP in primary CD4+ T cells identifies enhancer-gene interactions from dermatologic SNPs. (a) H3K27ac HiChIP experimental outline (red dot = H3K27ac-associated looping complex; blue dot = biotin; green semicircle = paired-end sequencing). (b) Number of total noncoding SNPs (left), HiChIP-genes (middle), and gene to SNP ratios (right) from inflammatory and nonimmune dermatologic conditions. (c) H3K27ac ChIP signal bias in T-cell subtypes for SNP-TSS pairs (proportion of strongest interactions, left; proportion of overall signal intensity, right). ChIP, chromatin immunoprecipitation; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; TH, T helper cell; Treg, regulatory T cell; TSS, transcription start site. Journal of Investigative Dermatology 2019 139, 605-614DOI: (10.1016/j.jid.2018.09.011) Copyright © 2018 The Authors Terms and Conditions

Figure 2 GWAS-identified SNPs from inflammatory conditions are strongly enriched in the HLA locus. (a) SNPs localized to the HLA locus from inflammatory (red) or nonimmune (blue) dermatologic conditions. (b) Percentage (and number) of HiChIP-genes found in the HLA locus. (c) Average gene to SNP ratio for inflammatory dermatologic conditions. (d) Number of HiChIP-gene targets versus nearest mapped (top) and author-reported genes (bottom) for all inflammatory HiChIP SNPs in the HLA locus. (e) Interaction profile (HiChIP v4C visualization, H3K27ac ChIP-seq, ATAC-seq) of HLA gene promoters was generated with corresponding GWAS-identified SNPs. (f) Whole-blood expression quantitative trait loci (eQTL) box plot of association between rs3129763 and HLA-DQB1 expression from the Genotype-Tissue Expression (GTEx). ATAC, assay for transposase-accessible chromatin; ChIP, chromatin immunoprecipitation; Chr., chromosome; HiChIP-gene, HiChIP-identified putative target genes; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; S. Sclerosis; systemic sclerosis; RefSeq, Reference Sequence database; TH, T helper cell; Treg, regulatory T cell; Journal of Investigative Dermatology 2019 139, 605-614DOI: (10.1016/j.jid.2018.09.011) Copyright © 2018 The Authors Terms and Conditions

Figure 3 Pathway analysis of HiChIP-genes shared among inflammatory conditions identifies the JAK-STAT signaling pathway. (a) The number of HiChIP-genes that are shared between two, three, or four different inflammatory conditions, after adjusting for the HLA locus. (b) Inflammatory conditions with HiChIP-genes in the JAK-STAT signaling pathway. (c, d) Interaction profiles (HiChIP v4C visualization, H3K27ac ChIP-seq, ATAC-seq) of the (c) cytokine receptor (IFNGR1 and IL15RA) promoters and (d) transcription factors (STAT1 and STAT4) were generated with corresponding GWAS-identified SNPs. ATAC, assay for transposase-accessible chromatin; ChIP, chromatin immunoprecipitation; Chr., chromosome; EIS, enhancer interaction signal; eQTL, expression quantitative trait loci; HiChIP-gene, HiChIP-identified putative target gene; Norm, normalized; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; S. Sclerosis; systemic sclerosis; RefSeq, Reference Sequence database; TH, T helper cell; Treg, regulatory T cell; v4C, virtual 4C. Journal of Investigative Dermatology 2019 139, 605-614DOI: (10.1016/j.jid.2018.09.011) Copyright © 2018 The Authors Terms and Conditions

Figure 4 Enhancer connectome identifies transcription factors involved in CD4+ T-cell differentiation from SLE SNPs. (a) Gene ontology (GO) analysis of SLE HiChIP-genes, with corresponding enrichment significance and number of genes for each term. (b, c) Interaction profiles (HiChIP v4C visualization, H3K27ac ChIP-seq, ATAC-seq) of (b) IRF8 and (c) IKZF1/2/3 were generated with corresponding GWAS-identified SNPs. ChIP, chromatin immunoprecipitation; Chr., chromosome; EIS, enhancer interaction signal; GWAS, genome-wide association study; HiChIP-gene, HiChIP-identified putative target gene; RefSeq, Reference Sequence database; seq, sequencing; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; v4C, virtual 4C. Journal of Investigative Dermatology 2019 139, 605-614DOI: (10.1016/j.jid.2018.09.011) Copyright © 2018 The Authors Terms and Conditions