NRSF/REST-Mediated Epigenomic Regulation in the Heart: Transcriptional Control of Natriuretic Peptides and Beyond.
NRSF/REST-Mediated Epigenomic Regulation in the Heart: Transcriptional Control of Natriuretic Peptides and Beyond.
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DOI：
10.3390/biology11081197
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发表时间：
2022-08-10
期刊：
影响因子：
4.2
通讯作者：
Kuwahara, Koichiro
中科院分区：
文献类型：
--
作者：
Inazumi, Hideaki;Kuwahara, Koichiro
胎儿心脏基因程序的重新激活，例如编码心房肽和脑钠肽（分别为 ANP 和 BNP）的基因程序，是心脏衰竭的一个特征。我们之前揭示了转录抑制因子神经元限制性沉默因子（NRSF），也称为抑制元件1沉默转录因子（REST），通过与其他各种转录因子的协作，在ANP、BNP和其他胎儿心脏基因的转录控制中发挥着至关重要的作用，以维持生理心脏功能和电稳定性。 ANP 和 BNP 生成的增加可防止心力衰竭的进展，但 Gαo 和胎儿型心脏离子通道（T 型 Ca2+ 和 HCN 通道）的重新激活会导致心脏功能恶化，并在 NRSF 功能紊乱的小鼠中观察到致命性心律失常。与 NRSF 形成复合体的表观遗传调节因子可修饰组蛋白乙酰化和甲基化，从而参与 NRSF 介导的转录调控。进一步的综合研究将有助于阐明心功能障碍和心力衰竭发展的分子机制。胎儿心脏基因的重新激活，包括编码心房钠尿肽（ANP）和脑钠尿肽（BNP）的基因，是病理性心脏重塑和心力衰竭的关键特征。对 ANP 和 BNP 调节的深入研究表明，许多转录因子参与胎儿心脏基因程序的调节。其中，我们发现了一种转录抑制因子，神经元限制性沉默因子（NRSF），也称为抑制元件-1-沉默转录因子（REST），最初被检测为非神经元细胞中神经元特异性基因的转录抑制因子，在ANP、BNP和其他胎儿心脏基因的转录调节中发挥着关键作用。本文综述了ANP和BNP基因表达的转录调控以及NRSF阻遏物复合物在心脏基因表达调节和维持心脏稳态中的作用。
Reactivation of the fetal cardiac gene program, such as those encoding atrial and brain natriuretic peptides (ANP and BNP, respectively), is a characteristic feature of failing hearts. We previously revealed that a transcriptional repressor, neuron-restrictive silencer factor (NRSF), also called repressor element-1-silencing transcription factor (REST), plays a crucial role in the transcriptional control of ANP, BNP and other fetal cardiac genes through collaboration with various other transcription factors to maintain physiological cardiac function and electrical stability. Increased production of ANP and BNP prevents the progression of heart failure, but reactivation of Gαo and fetal-type cardiac ion channels (T-type Ca2+ and HCN channels) leads to deteriorated cardiac function and lethal arrhythmias observed in mice with disturbed NRSF function. Epigenetic regulators with which NRSF forms a complex modify histone acetylation and methylation, thereby participating in NRSF-mediated transcriptional regulation. Further comprehensive studies will lead to clarification of the molecular mechanisms underlying the development of cardiac dysfunction and heart failure. Reactivation of fetal cardiac genes, including those encoding atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), is a key feature of pathological cardiac remodeling and heart failure. Intensive studies on the regulation of ANP and BNP have revealed the involvement of numerous transcriptional factors in the regulation of the fetal cardiac gene program. Among these, we identified that a transcriptional repressor, neuron-restrictive silencer factor (NRSF), also named repressor element-1-silencing transcription factor (REST), which was initially detected as a transcriptional repressor of neuron-specific genes in non-neuronal cells, plays a pivotal role in the transcriptional regulation of ANP, BNP and other fetal cardiac genes. Here we review the transcriptional regulation of ANP and BNP gene expression and the role of the NRSF repressor complex in the regulation of cardiac gene expression and the maintenance of cardiac homeostasis.
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