The neuron-restrictive silencer element-neuron-restrictive silencer factor system regulates basal and endothelin 1-inducible atrial natriuretic peptide gene expression in ventricular myocytes
The neuron-restrictive silencer element-neuron-restrictive silencer factor system regulates basal and endothelin 1-inducible atrial natriuretic peptide gene expression in ventricular myocytes
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DOI：
10.1128/mcb.21.6.2085-2097.2001
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发表时间：
2001-03-01
影响因子：
5.3
通讯作者：
Nakao, K
中科院分区：
文献类型：
--
作者：
Kuwahara, K;Saito, Y;Nakao, K
心钠素(ANP)基因的诱导是心肌肥厚的共同特征。一些转录激活子的顺式作用增强子元件已被证明在ANP基因表达的调控中发挥核心作用，但对转录抑制因子的贡献知之甚少。神经元限制性沉默元件(NRSE)，也被称为抑制元件1，在非神经元细胞中介导抑制神经元基因的表达。我们发现，位于ANP基因3‘端非翻译区的NRSE介导了对心肌细胞ANP启动子活性的抑制，也参与了内皮素1诱导的ANP基因转录的增加。这种抑制是由一种抑制蛋白--神经元限制性沉默因子(NRSF)实现的。NRSF与转录辅阻遏子mSin3结合，并与组蛋白脱乙酰酶(HDAC)在心室肌细胞中形成复合体。HDAC特异性抑制剂曲古抑素A(TSA)可解除NRSE对ANP启动子活性的抑制，染色质免疫沉淀分析显示组蛋白去乙酰化参与了NRSE对ANP基因表达的抑制。此外，与对照组相比，表达显性-阴性形式NRSF的重组腺病毒感染心肌细胞后，内源性ANP基因表达的基础水平VAS增加，TSA诱导的ANP基因表达增加的作用明显减弱。我们的发现表明，NRSE-NRSF系统在HDAC对心肌细胞ANP基因表达的调控中起着关键作用，并为了解NRSE-NRSF系统在神经系统外的作用提供了新的视角。
Induction of the atrial natriuretic peptide (ANP) gene is a common feature of ventricular hypertrophy. A number of cis acting enhancer elements for several transcriptional activators have been shown to play central roles in the regulation of ANP gene expression, but much less is known about contributions made by transcriptional repressors. The neuron-restrictive silencer element (NRSE), also known as repressor element 1, mediates repression of neuronal gene expression in nonneuronal cells. We found that NRSE, which is located in the 3 ' untranslated region of the ANP gene, mediated repression of ANP promoter activity in ventricular myocytes and was also involved in the endothelin 1-induced increase in ANP gene transcription. The repression was conferred by a repressor protein, neuron-restrictive silencer factor (NRSF). NRSF associated with the transcriptional corepressor mSin3 and formed a complex with histone deacetylase (HDAC) in ventricular myocytes. Trichostatin A (TSA), a specific HDAC inhibitor, relieved NRSE-mediated repression of ANP promoter activity, and chromatin immunoprecipitation assays revealed the involvement of histone deacetylation in NRSE-mediated repression of ANP gene expression. Furthermore, in myocytes infected with recombinant adenovirus expressing a dominant-negative form of NRSF, the basal level of endogenous ANP gene expression,vas increased and a TSA-induced increase in ANP gene expression was apparently attenuated, compared with those in myocytes infected with control adenovirus. Our findings show that an NRSE-NRSF system plays a key role in the regulation of ANP gene expression by HDAC in ventricular myocytes and provide a new insight into the role of the NRSE-NRSF system outside the nervous system.