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首页> 外文期刊>Molecular and Cellular Biology >Histone Deacetylase 3 Interacts with and Deacetylates Myocyte Enhancer Factor 2
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Histone Deacetylase 3 Interacts with and Deacetylates Myocyte Enhancer Factor 2

机译：组蛋白脱乙酰基酶3与心肌细胞增强因子2相互作用并使其脱乙酰基

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The myocyte enhancer factor 2 (MEF2) family of transcription factors is not only important for controlling gene expression in normal cellular programs, like muscle differentiation, T-cell apoptosis, neuronal survival, and synaptic differentiation, but has also been linked to cardiac hypertrophy and other pathological conditions. Lysine acetylation has been shown to modulate MEF2 function, but it is not so clear which deacetylase(s) is involved. We report here that treatment of HEK293 cells with trichostatin A or nicotinamide upregulated MEF2D acetylation, suggesting that different deacetylases catalyze the deacetylation. Related to the trichostatin A sensitivity, histone deacetylase 4 (HDAC4) and HDAC5, two known partners of MEF2, exhibited little deacetylase activity towards MEF2D. In contrast, HDAC3 efficiently deacetylated MEF2D in vitro and in vivo. This was specific, since HDAC1, HDAC2, and HDAC8 failed to do so. While HDAC4, HDAC5, HDAC7, and HDAC9 are known to recognize primarily the MEF2-specific domain, we found that HDAC3 interacts directly with the MADS box. In addition, HDAC3 associated with the acetyltransferases p300 and p300/CBP-associated factor (PCAF) to reverse autoacetylation. Furthermore, the nuclear receptor corepressor SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) stimulated the deacetylase activity of HDAC3 towards MEF2 and PCAF. Supporting the physical interaction and deacetylase activity, HDAC3 repressed MEF2-dependent transcription and inhibited myogenesis. These results reveal an unexpected role for HDAC3 and suggest a novel pathway through which MEF2 activity is controlled in vivo.
机译：肌细胞增强因子2（MEF2）家族的转录因子不仅对于控制正常细胞程序中的基因表达（例如肌肉分化，T细胞凋亡，神经元存活和突触分化）很重要，而且还与心脏肥大和其他病理状况。赖氨酸乙酰化已被证明可调节MEF2功能，但尚不清楚涉及哪些脱乙酰基酶。我们在这里报告，用曲古抑菌素A或烟酰胺治疗HEK293细胞上调了MEF2D乙酰化作用，表明不同的脱乙酰基酶催化了脱乙酰基作用。与曲古抑素A敏感性相关的是，MEF2的两个已知伙伴组蛋白脱乙酰基酶4（HDAC4）和HDAC5对MEF2D几乎没有脱乙酰基酶活性。相反，HDAC3在体外和体内有效地使MEF2D脱乙酰。这是特定的，因为HDAC1，HDAC2和HDAC8无法这样做。虽然已知HDAC4，HDAC5，HDAC7和HDAC9主要识别MEF2特定域，但我们发现HDAC3与MADS框直接交互。此外，HDAC3与乙酰基转移酶p300和p300 / CBP相关因子（PCAF）相关，可逆转自体乙酰化。此外，核受体共抑制物SMRT（类维生素A酸和甲状腺激素受体的沉默介质）刺激了HDAC3对MEF2和PCAF的脱乙酰酶活性。支持物理相互作用和脱乙酰酶活性，HDAC3抑制了MEF2依赖性转录并抑制了肌发生。这些结果揭示了HDAC3出乎意料的作用，并提出了一种在体内控制MEF2活性的新途径。

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