Enhancer Turnover Is Associated with a Divergent Transcriptional Response to Glucocorticoid in Mouse and Human Macrophages.
Enhancer Turnover Is Associated with a Divergent Transcriptional Response to Glucocorticoid in Mouse and Human Macrophages.
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DOI：
10.4049/jimmunol.1502009
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发表时间：
2016-01-15
期刊：
影响因子：
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通讯作者：
Bickmore WA
中科院分区：
文献类型：
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作者：
Jubb AW;Young RS;Hume DA;Bickmore WA
个体和物种之间的表型差异部分是通过一组相对保守的基因的表达差异来控制的。在免疫系统中表达的基因受到特别强大的选择。我们已经研究了暴露于糖皮质激素（GC）的人类和小鼠巨噬细胞中基因表达和候选增强子的演变，糖皮质激素是先天免疫的调节剂和重要的治疗剂。我们的分析显示，在人类和小鼠巨噬细胞中，对GC反应的基因库的重叠非常有限。通过ChIP-Seq检测到的糖皮质激素受体（GR）的诱导性结合峰与两个物种中靶基因的诱导相关，但不与抑制相关，发生在远端调控位点而不是启动子处，并且强烈富集共有GR结合基序。小鼠和人之间GR结合的周转与基序的获得和丧失相关。在物种特异性GR结合位点没有检测到正选择信号，但在少数保守位点有明显的纯化选择证据。我们的结论是增强子分歧的基础上的差异，在小鼠和人的巨噬细胞之间的GC处理后的转录激活。只有共享的诱导基因座显示出选择的证据，因此这些基因座对于物种之间共享的GC反应子集可能是重要的。
Phenotypic differences between individuals and species are controlled in part through differences in expression of a relatively conserved set of genes. Genes expressed in the immune system are subject to especially powerful selection. We have investigated the evolution of both gene expression and candidate enhancers in human and mouse macrophages exposed to glucocorticoid (GC), a regulator of innate immunity and an important therapeutic agent. Our analyses revealed a very limited overlap in the repertoire of genes responsive to GC in human and mouse macrophages. Peaks of inducible binding of the glucocorticoid receptor (GR) detected by ChIP-Seq correlated with induction, but not repression, of target genes in both species, occured at distal regulatory sites not promoters, and were strongly enriched for the consensus GR binding motif. Turnover of GR binding between mouse and human was associated with gain and loss of the motif. There was no detectable signal of positive selection at species-specific GR binding sites, but clear evidence of purifying selection at the small number of conserved sites. We conclude that enhancer divergence underlies the difference in transcriptional activation after GC treatment between mouse and human macrophages. Only the shared inducible loci show evidence of selection and therefore these loci may be important for the subset of responses to GC that is shared between species.