Department of Otorhinolaryngology, Jikei University School of Medicine, Tokyo, Japan.
Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
J Assoc Res Otolaryngol. 2021 Jul;22(4):405-424. doi: 10.1007/s10162-021-00801-7. Epub 2021 Apr 16.
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 the FOXC2 loci, 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.
不同的组蛋白修饰调节某些疾病中的基因表达，但中耳胆脂瘤中的组蛋白表观遗传学知之甚少。已知组蛋白乙酰化使核小体和染色质结构不稳定，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有关。在这项研究中，我们通过免疫组织化学检查了人中耳胆脂瘤（胆脂瘤）组织和胆脂瘤动物模型的石蜡包埋切片中各种修饰的组蛋白 H3 乙酰化在赖氨酸 9、14、18、23 和 27 处的定位。结果发现，H3K27ac 在人胆脂瘤组织和动物模型中的表达水平均显著增加。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 染色质免疫沉淀测序来绘制人胆脂瘤中的活性顺式调控景观。基于这些结果，我们确定了增加的 H3K27ac 信号作为 FOXC2 基因座的超级增强子，以及胆脂瘤中 FOXC2 蛋白的增加。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 menin-MLL 抑制剂在体内抑制 FOXC2 的表达。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。
