Long-range enhancer associated with chromatin looping allows AP-1 regulation of the peptidylarginine deiminase 3 gene in differentiated keratinocyte.
Long-range enhancer associated with chromatin looping allows AP-1 regulation of the peptidylarginine deiminase 3 gene in differentiated keratinocyte.
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与染色质环相关的远距离增强子可以调节分化角蛋白形成细胞中肽基金氨酸脱氨酶3基因。
DOI：
10.1371/journal.pone.0003408
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Simon, Michel
中科院分区：
文献类型：
--
作者：
Chavanas, Stephane;Adoue, Veronique;Mechin, Marie-Claire;Ying, Shibo;Dong, Sijun;Duplan, Helene;Charveron, Marie;Takahara, Hidenari;Serre, Guy;Simon, Michel
远距离的转录控制是一种关键机制，特别是对于连续基因。肽基精氨酸脱亚胺酶（PAD）催化蛋白结合精氨酸转化为瓜氨酸（脱亚胺），这是多发性硬化症、阿尔茨海默病和类风湿性关节炎的病理生理学中的关键反应，也是主要表皮屏障蛋白聚丝蛋白代谢中的关键反应，聚丝蛋白是特应性皮炎的强烈易感因素。PADs由5个聚簇的PADI基因（1 p35 -6）编码。不清楚的是控制基因PADI 3的表达的机制，编码PAD 3同种型，一个强有力的候选人在终末分化的表皮角质形成细胞中的聚丝蛋白脱亚氨基。我们描述了第一个PAD基因间增强子（PIE），一个进化上保守的非编码片段，位于PADI 3启动子的86-kb处。PIE是Ca 2+分化的表皮角质形成细胞中PADI 3启动子的强增强子，并且需要结合的AP-1因子，即c-Jun和c-Fos。与增殖性角质形成细胞相比，钙刺激与PIE周围局部DNA酶I超敏性增加以及PIE和PADI 3的物理接近性增加（通过染色体构象捕获评估）特异性相关。特异性AP-1抑制剂去甲二氢愈创木酸抑制角质形成细胞中钙诱导的PADI 3 mRNA水平增加。我们的研究结果为探索肿瘤发生和伤口愈合过程中的脱亚氨基控制铺平了道路，这两种情况下AP-1因子是至关重要的，并揭示了远程转录控制在基因PADI 3的调节中起作用。由于远端调节剂失效会导致多种人类疾病，因此PIE结果在脱亚胺相关疾病或特应性疾病的关联研究中是一个合理的候选者。
Transcription control at a distance is a critical mechanism, particularly for contiguous genes. The peptidylarginine deiminases (PADs) catalyse the conversion of protein-bound arginine into citrulline (deimination), a critical reaction in the pathophysiology of multiple sclerosis, Alzheimer's disease and rheumatoid arthritis, and in the metabolism of the major epidermal barrier protein filaggrin, a strong predisposing factor for atopic dermatitis. PADs are encoded by 5 clustered PADI genes (1p35-6). Unclear are the mechanisms controlling the expression of the gene PADI3 encoding the PAD3 isoform, a strong candidate for the deimination of filaggrin in the terminally differentiating epidermal keratinocyte. We describe the first PAD Intergenic Enhancer (PIE), an evolutionary conserved non coding segment located 86-kb from the PADI3 promoter. PIE is a strong enhancer of the PADI3 promoter in Ca2+-differentiated epidermal keratinocytes, and requires bound AP-1 factors, namely c-Jun and c-Fos. As compared to proliferative keratinocytes, calcium stimulation specifically associates with increased local DNase I hypersensitivity around PIE, and increased physical proximity of PIE and PADI3 as assessed by Chromosome Conformation Capture. The specific AP-1 inhibitor nordihydroguaiaretic acid suppresses the calcium-induced increase of PADI3 mRNA levels in keratinocytes. Our findings pave the way to the exploration of deimination control during tumorigenesis and wound healing, two conditions for which AP-1 factors are critical, and disclose that long-range transcription control has a role in the regulation of the gene PADI3. Since invalidation of distant regulators causes a variety of human diseases, PIE results to be a plausible candidate in association studies on deimination-related disorders or atopic disease.
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影响因子：
3.5
作者：
Chavanas, S;Méchin, MC;Simon, M
通讯作者：
Simon, M
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