Modulation of chromatin position and gene expression by HDAC4 interaction with nucleoporins
Modulation of chromatin position and gene expression by HDAC4 interaction with nucleoporins
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DOI：
10.1083/jcb.201101046
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发表时间：
2011-04-04
影响因子：
7.8
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
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作者：
Kehat, Izhak;Accornero, Federica;Molkentin, Jeffery D.
IIa类组蛋白去乙酰化酶（HDACs）能够调节染色质结构和转录活性，从而参与细胞反应的调控，比如心肌细胞肥大。然而，控制诱导性心脏生长的IIa类HDACs的靶基因，以及这些去乙酰化酶在染色质内调节基因位点特异性表达的更广泛机制仍然是个谜。在此，我们利用全基因组启动子占位分析、表达谱分析以及原代细胞验证来确定心肌细胞中IIa类HDAC4的直接靶基因。同时，我们确定核孔蛋白155（Nup155）是一种与HDAC4相互作用的蛋白质。从机制上讲，我们表明HDAC4通过与Nup155相互作用来调节已确定的靶基因与核孔蛋白的关联。此外，一种不能结合HDAC4的Nup155截短突变体抑制了HDAC4诱导的基因表达模式以及染色质 - 核孔蛋白的关联，这表明Nup155介导的定位是HDAC4对基因表达产生影响所必需的。因此，我们提出了HDAC4的一种新的作用机制，表明它能够通过改变染色质 - 核孔蛋白的关联来动态调节基因表达。
Class IIa histone deacetylases (HDACs) can modulate chromatin architecture and transcriptional activity, thereby participating in the regulation of cellular responses such as cardiomyocyte hypertrophy. However, the target genes of class IIa HDACs that control inducible cardiac growth and the broader mechanisms whereby these deacetylases modulate locus-specific gene expression within chromatin remain a mystery. Here, we used genome-wide promoter occupancy analysis, expression profiling, and primary cell validation to identify direct class IIa HDAC4 targets in cardiomyocytes. Simultaneously, we identified nucleoporin155 (Nup155) as an HDAC4-interacting protein. Mechanistically, we show that HDAC4 modulated the association of identified target genes with nucleoporins through interaction with Nup155. Moreover, a truncated mutant of Nup155 that cannot bind HDAC4 suppressed HDAC4-induced gene expression patterns and chromatin-nucleoporin association, suggesting that Nup155-mediated localization was required for HDAC4's effect on gene expression. We thus propose a novel mechanism of action for HDAC4, suggesting it can function to dynamically regulate gene expression through changes in chromatin-nucleoporin association.