Zinc-finger protein 90 negatively regulates neuron-restrictive silencer factor-mediated transcriptional repression of fetal cardiac genes
Zinc-finger protein 90 negatively regulates neuron-restrictive silencer factor-mediated transcriptional repression of fetal cardiac genes
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DOI：
10.1016/j.yjmcc.2011.01.017
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发表时间：
2011-06-01
影响因子：
5
通讯作者：
Nakao, Kazuwa
中科院分区：
文献类型：
--
作者：
Hata, Leo;Murakami, Masao;Nakao, Kazuwa
神经元限制性沉默因子（NRSF）是一种锌指转录因子，与特定的DNA序列（NRSE）结合抑制转录。通过下调其靶基因的转录，NRSF有助于调节各种生物学过程，包括神经元分化、癌发生和心血管稳态。我们以前报道过NRSF调节心脏胎儿基因程序的表达，并且NRSF介导的抑制的减弱有助于在病理条件下心脏的遗传重构。然而，在心脏病理条件下调节NRSF活性的精确分子机制和信号通路仍不清楚。本研究以NRSF为诱饵，利用酵母双杂交技术筛选了NRSF的调控蛋白，并鉴定了一个新的NRSF结合蛋白锌指蛋白（Zfp）90。NRSF和Zfp90共定位于细胞核中，前者的锌指DNA结合结构域与后者特异性相互作用。Zfp90通过抑制NRSF与DNA的结合来抑制NRSF的阻遏物活性，从而解除NRSF靶基因的转录抑制。Zfp90的siRNA敲低导致NRSF靶向胎儿心脏基因、心房和脑钠肽基因的表达减少，相反，Zfp90在心室肌中的过表达导致这些基因的表达显著增加。值得注意的是，Zfp90 mRNA的表达在患有慢性心力衰竭的小鼠和人类心脏中显著上调。总的来说，这些结果表明，Zfp90作为NRSF的负调节剂发挥作用，并有助于心脏功能障碍发展过程中的遗传重构。(C)2011爱思唯尔有限公司版权所有。
Neuron-restrictive silencer factor (NRSF) is a zinc-finger transcription factor that binds to specific DNA sequences (NRSE) to repress transcription. By down-regulating the transcription of its target genes, NRSF contributes to the regulation of various biological processes, including neuronal differentiation, carcinogenesis and cardiovascular homeostasis. We previously reported that NRSF regulates expression of the cardiac fetal gene program, and that attenuation of NRSF-mediated repression contributes to genetic remodeling in hearts under pathological conditions. The precise molecular mechanisms and signaling pathways via which NRSF activity is regulated in pathological conditions of the heart remain unclear, however. In this study, to search for regulators of NRSF, we carried out yeast two-hybrid screening using NRSF as bait and identified zinc-finger protein (Zfp) 90 as a novel NRSF-binding protein. NRSF and Zfp90 colocalized in the nucleus, with the zinc-finger DNA-binding domain of the former specifically interacting with the latter. Zfp90 inhibited the repressor activity of NRSF by inhibiting its binding to DNA, thereby derepressing transcription of NRSF-target genes. Knockdown of Zfp90 by siRNA led to reduced expression of NRSF-target fetal cardiac genes, atrial and brain natriuretic peptide genes, and conversely, overexpression of Zfp90 in ventricular myocardium resulted in significant increases in the expression of these genes. Notably, expression of Zfp90 mRNA was significantly upregulated in mouse and human hearts with chronic heart failure. Collectively, these results suggest that Zfp90 functions as a negative regulator of NRSF and contributes to genetic remodeling during the development of cardiac dysfunction. (C) 2011 Elsevier Ltd. All rights reserved.