Endothelin-stimulated human B-type natriuretic peptide gene expression is mediated by Yin Yang 1 in association with histone deacetylase 2.
Endothelin-stimulated human B-type natriuretic peptide gene expression is mediated by Yin Yang 1 in association with histone deacetylase 2.
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DOI：
10.1161/hypertensionaha.108.125088
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发表时间：
2009-03
期刊：
影响因子：
--
通讯作者：
Gardner DG
中科院分区：
文献类型：
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作者：
Glenn DJ;Wang F;Chen S;Nishimoto M;Gardner DG
B型钠尿肽（BNP）基因表达增加被认为是心肌细胞肥大的标志之一。在这里，我们证明人类 (h) BNP 基因转录的基础和内皮素 1 (ET-1) 依赖性刺激需要存在完整的阴阳 1 (YY1) 结合位点，该结合位点相对于转录起始位点位于 -62 bp。该位点的突变降低了 hBNP 启动子的基础活性和刺激性 hBNP 启动子活性。该位点在体外和完整细胞内均显示出与 YY1 的结合。 ET-1 治疗后后一种相互作用增加。暴露于 ET-1 还导致 YY1 核定位增加和 YY1 蛋白乙酰化减少。野生型YY1的过表达增加了基础和内皮素刺激的hBNP启动子活性，而YY1的羧基末端缺失突变体则缺乏活性。组蛋白脱乙酰酶抑制剂曲古抑菌素 A (TSA) 治疗导致 hBNP 报告基因活性降低。 YY1 显示与组蛋白脱乙酰酶 2 (HDAC2) 相关，而 HDAC2 显示与完整细胞中的 hBNP 启动子直接相关。总的来说，这些发现表明 YY1 在调节 hBNP 基因启动子的转录活性中发挥着重要作用。这些数据表明 YY1 通过与 HDAC2 相互作用激活 hBNP 转录。
Increased B-type natriuretic peptide (BNP) gene expression is regarded as one of the hallmarks of cardiac myocyte hypertrophy. Here we demonstrate that both basal and endothelin-1 (ET-1) -dependent stimulation of human (h) BNP gene transcription requires the presence of an intact Yin Yang 1 (YY1) binding site positioned at -62 bp relative to the transcription start site. Mutation of this site reduced both basal and stimulated hBNP promoter activity. This site was shown to bind YY1 both in vitro and within the context of the intact cell. The latter interaction increased following ET-1 treatment. Exposure to ET-1 also resulted in increased nuclear localization of YY1 and a reduction in acetylation of the YY1 protein. Overexpression of wild type YY1 increased both basal and endothelin-stimulated hBNP promoter activity, while a carboxy terminal deletion mutant of YY1 was devoid of activity. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) resulted in decreased hBNP reporter activity. YY1 was shown to associate with histone deacetylase 2 (HDAC2), and HDAC2 was shown to associate directly with the hBNP promoter in the intact cell. Collectively these findings demonstrate that YY1 plays an important role in regulating the transcriptional activity of the hBNP gene promoter. These data suggest a model in which YY1 activates hBNP transcription through interaction with HDAC2.