A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages.
A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages.
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DOI：
10.1101/gad.257592.114
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发表时间：
2015-02-15
影响因子：
10.5
通讯作者：
Natoli G
中科院分区：
文献类型：
--
作者：
Mancino A;Termanini A;Barozzi I;Ghisletti S;Ostuni R;Prosperini E;Ozato K;Natoli G
转录因子IRF8控制巨噬细胞的发育和炎症刺激诱导基因。Mancino等人发现，在脂多糖（LPS）刺激前后，IRF8被招募到不同的DNA共识序列。而组成性表达的IRF8依赖基因只包含介导基础IRF8/PU的位点。1招募，诱导的irf8依赖基因包含组成位点和诱导位点的可变组合。转录因子（TF）干扰素调节因子8 （IRF8）控制巨噬细胞的发育和炎症刺激诱导基因，但这两种不同功能的机制在很大程度上是未知的。一种可能性是，这些不同的作用与IRF8结合其他DNA序列的能力有关。我们发现，在脂多糖（LPS）刺激前后，IRF8被招募到不同的DNA共识序列集。在静息细胞中，IRF8主要与髓系发育主调控因子PU.1结合到复合位点。基底IRF8-PU。1结合维持巨噬细胞功能（如微生物识别和对嘌呤的反应）所必需的广泛基因的表达，并有助于许多lps诱导基因的基础表达。在LPS刺激后，IRF8、其他IRF和AP-1家族tf的表达增加，使IRF8结合到数千个含有低亲和多聚IRF位点和复合IRF - AP-1位点的额外区域，这些区域没有被PU.1预先标记，也不参与基础IRF8细胞凋亡。而组成性表达的IRF8依赖基因只包含介导基础IRF8/PU的位点。1招募，诱导的irf8依赖基因包含组成位点和诱导位点的可变组合。总的来说，这些数据表明，在基因组尺度上，相同的TF如何通过不同的dna结合位点的不同组合与组成型和诱导型基因调控相关联。
The transcription factor IRF8 controls both developmental and inflammatory stimulus-inducible genes in macrophages. Mancino et al. found that IRF8 is recruited to distinct sets of DNA consensus sequences before and after lipopolysaccharide (LPS) stimulation. While constitutively expressed IRF8-dependent genes contained only sites mediating basal IRF8/PU.1 recruitment, inducible IRF8-dependent genes contained variable combinations of constitutive and inducible sites. The transcription factor (TF) interferon regulatory factor 8 (IRF8) controls both developmental and inflammatory stimulus-inducible genes in macrophages, but the mechanisms underlying these two different functions are largely unknown. One possibility is that these different roles are linked to the ability of IRF8 to bind alternative DNA sequences. We found that IRF8 is recruited to distinct sets of DNA consensus sequences before and after lipopolysaccharide (LPS) stimulation. In resting cells, IRF8 was mainly bound to composite sites together with the master regulator of myeloid development PU.1. Basal IRF8–PU.1 binding maintained the expression of a broad panel of genes essential for macrophage functions (such as microbial recognition and response to purines) and contributed to basal expression of many LPS-inducible genes. After LPS stimulation, increased expression of IRF8, other IRFs, and AP-1 family TFs enabled IRF8 binding to thousands of additional regions containing low-affinity multimerized IRF sites and composite IRF–AP-1 sites, which were not premarked by PU.1 and did not contribute to the basal IRF8 cistrome. While constitutively expressed IRF8-dependent genes contained only sites mediating basal IRF8/PU.1 recruitment, inducible IRF8-dependent genes contained variable combinations of constitutive and inducible sites. Overall, these data show at the genome scale how the same TF can be linked to constitutive and inducible gene regulation via distinct combinations of alternative DNA-binding sites.
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作者：
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Glass CK