Super-enhancer Acquisition Drives FOXC2 Expression in Middle Ear Cholesteatoma
Super-enhancer Acquisition Drives FOXC2 Expression in Middle Ear Cholesteatoma
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DOI：
10.1007/s10162-021-00801-7
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发表时间：
2021-04
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影响因子：
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通讯作者：
Tomomi Yamamoto-Fukuda;Naotaro Akiyama;H. Kojima
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作者：
Tomomi Yamamoto-Fukuda;Naotaro Akiyama;H. Kojima
不同的组蛋白修饰调节某些疾病中的基因表达，但人们对中耳胆脂瘤中的组蛋白表观遗传学知之甚少。众所周知，组蛋白乙酰化会破坏核小体和染色质结构的稳定性并诱导基因激活。最近的研究表明组蛋白乙酰化与慢性炎症性疾病之间存在关联。在本研究中，我们通过免疫组织化学方法检测了人中耳胆脂瘤组织和胆脂瘤动物模型颞骨石蜡包埋切片中赖氨酸 9、14、18、23 和 27 处不同修饰的组蛋白 H3 乙酰化的定位。结果，我们发现人胆脂瘤组织和动物模型中 H3K27ac 的表达水平显着增加。在遗传学中，超级增强子是驱动细胞身份相关基因转录的增强子簇。超级增强子最初是使用 H3K27ac 信号定义的，然后我们使用 H3K27ac 染色质免疫沉淀和测序来绘制人类胆脂瘤中活跃的顺式调控景观。根据结果，我们确定胆脂瘤中 H3K27ac 信号增加是 FOXC2 基因座的超级增强子，并且 FOXC2 蛋白增加。最近的研究表明 menin-MLL 抑制剂可以通过控制组蛋白 H3 修饰来抑制肿瘤生长。在这项研究中，我们证明了FOXC2的表达在体内被menin-MLL抑制剂抑制。这些发现表明组蛋白修饰下的FOXC2表达促进了胆脂瘤的发病机制，并表明它可能是胆脂瘤的治疗靶点。
Distinct histone modifications regulate gene expression in certain diseases, but little is known about histone epigenetics in middle ear cholesteatoma. It is known that histone acetylation destabilizes the nucleosome and chromatin structure and induces gene activation. The association of histone acetylation with chronic inflammatory diseases has been indicated in recent studies. In this study, we examined the localization of variously modified histone H3 acetylation at lysine 9, 14, 18, 23, and 27 in paraffin-embedded sections of human middle ear cholesteatoma (cholesteatoma) tissues and the temporal bones of an animal model of cholesteatoma immunohistochemically. As a result, we found that there was a significant increase of the expression levels of H3K27ac both in human cholesteatoma tissues and the animal model. In genetics, super-enhancers are clusters of enhancers that drive the transcription of genes involved in cell identity. Super-enhancers were originally defined using the H3K27ac signal, and then we used H3K27ac chromatin immunoprecipitation followed by sequencing to map the active cis-regulatory landscape in human cholesteatoma. Based on the results, we identified increased H3K27ac signals as super-enhancers of theFOXC2loci, as well as increased protein of FOXC2 in cholesteatoma. Recent studies have indicated that menin-MLL inhibitor could suppress tumor growth through the control of histone H3 modification. In this study, we demonstrated that the expression of FOXC2 was inhibited by menin-MLL inhibitor in vivo. These findings indicate that FOXC2 expression under histone modifications promoted the pathogenesis of cholesteatoma and suggest that it may be a therapeutic target of cholesteatoma.