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Mechanisms underlying strikingly divergent responses of genetically distinct macrophages to IL-4 [HiChIP]

ABSTRACT: Mechanisms by which non-coding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. To investigate these mechanisms with respect to signal-dependent gene expression, we evaluated effects of > 50 million SNPs and InDels provided by five inbred strains of mice on the responses of macrophages to the anti-inflammatory cytokine IL-4. Remarkably, of the > 600 genes observed to be induced >2-fold across the five strains after 24 hours of IL-4 treatment, only 26 genes reached this threshold in all strains and more than half of the induced genes were observed in only a single strain. By examining the effects of SNPs and InDels on transcription factor binding and enhancer activity under basal and IL-4 treatment conditions, we identified dominant collaborative roles of the signal-dependent transcription factors (SDTFs) STAT6, PPARg and EGR2 in driving late enhancer activation that were dependent on general macrophage lineage determining factors (LDTFs). As expected, SNPs and InDels that affected the relative affinities of SDTFs primarily influenced the ability of enhancers with similar basal activities to respond to IL-4. In contrast, SNPs and InDels that altered the relative binding affinities of macrophage LDTFs had divergent effects on basal and activated enhancer activity. Variants resulting in strong reductions in LDTF binding affinity were associated with low basal enhancer activity and failure to recruit SDTFs, whereas variants that increased LDTF binding affinities were associated with constitutively high levels of enhancer activity and a blunted response to SDTF recruitment. Together, these studies reveal mechanisms by which noncoding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-specific patterns of gene expression and phenotypic diversity.

ORGANISM(S): Mus musculus

PROVIDER: GSE159629 | GEO | 2021/06/19

REPOSITORIES: GEO

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Project description:Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations- we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at r^2≥0.5. Greater than 88% of the 727 SNPs fall within putative enhancers, many of which alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid in the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancer regions, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium (r^2=0.91) with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process. ChIP-seq analysis of H3K27Ac in LNCaP charcoal-stripped serum, H3K27Ac in LNCaP charcoal-stripped serum +DHT, TCF7L2 in LNCaP

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Mechanisms underlying strikingly divergent responses of genetically distinct macrophages to IL-4 [HiChIP]

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