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

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