Acute phase reactants (APRs) are secretory proteins exhibiting large expression changes in response to proinflammatory cytokines. Here we show that the expression pattern of a major APR, i.e. human C-reactive protein (CRP), is casually determined by DNMT3A and TET2-tuned promoter methylation status. CRP features a CpG-poor promoter with its CpG motifs located in binding sites of STAT3, C/EBP-β and NF-κB. These motifs are highly methylated at the resting state, but undergo STAT3- and NF-κB-dependent demethylation upon cytokine stimulation, leading to markedly enhanced recruitment of C/EBP-β that boosts CRP expression. Withdrawal of cytokines, by contrast, results in a rapid recovery of promoter methylation and termination of CRP induction. Further analysis suggests that reversible methylation also regulates the expression of highly inducible genes carrying CpG-poor promoters with APRs as representatives. Therefore, these CpG-poor promoters may evolve CpG-containing TF binding sites to harness dynamic methylation for prompt and reversible responses.

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可逆的启动子甲基化决定了急性期蛋白的波动表达

急性期反应物（APR）是分泌蛋白，对促炎性细胞因子有较大的表达变化。在这里，我们显示了主要APR的表达模式，即人C反应蛋白（CRP），由DNMT3A和TET2调节的启动子甲基化状态随意确定。CRP具有一个CpG弱启动子，其CpG基序位于STAT3，C /EBP-β和NF-κB的结合位点。这些基序在静止状态下高度甲基化，但在细胞因子刺激后经历STAT3和NF-κB依赖的去甲基化作用，导致C /EBP-β募集明显增强，从而增强CRP表达。相比之下，细胞因子的撤回导致启动子甲基化的快速恢复和CRP诱导的终止。进一步的分析表明，可逆的甲基化作用还调节了带有APR的CpG缺乏启动子的高诱导基因的表达。因此，这些缺乏CpG的启动子可能会进化出含有CpG的TF结合位点，以利用动态甲基化来实现迅速和可逆的响应。