Reversible promoter methylation determines fluctuating expression of acute phase proteins.
Reversible promoter methylation determines fluctuating expression of acute phase proteins.
复制标题
可逆的启动子甲基化决定了急性期蛋白的表达波动。
作者：
Zhang Shi-Chao;Wang Ming-Yu;Feng Jun-Rui;Chang Yue;Ji Shang-Rong;Wu Yi
急性期反应物（Acute phase reactors，APRs）是一种分泌性蛋白质，对促炎细胞因子的反应表现出较大的表达变化。在这里，我们表明，一个主要的人类APR，即C-反应蛋白（CRP）的表达模式，是偶然决定的DNMT 3A和TET 2调节启动子甲基化状态。CRP的启动子CpG基序位于STAT 3、C/EBP-β和NF-κB的结合位点。这些基序在静息状态下高度甲基化，但在细胞因子刺激后发生STAT 3和NF-κ B依赖性去甲基化，导致C/EBP-β的募集显著增强，从而促进CRP表达。相反，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，可逆甲基化也调控了携带CpG-贫启动子的高度诱导基因的表达，其中以APRs为代表。因此，这些CpG贫乏的启动子可能进化出含有CpG的TF结合位点，以利用动态甲基化来实现迅速和可逆的反应。
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 human APR, that is 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.