The hyper-activation of transcriptional enhancers in breast cancer
The hyper-activation of transcriptional enhancers in breast cancer
复制标题
乳腺癌中转录增强子的过度激活
DOI：
10.1186/s13148-019-0645-x
复制
发表时间：
2019-03-12
影响因子：
5.7
通讯作者：
Wu, Min
中科院分区：
文献类型：
--
作者：
Li, Qing-Lan;Wang, Dan-Ya;Wu, Min
背景转录增强子尤其是超级增强子的激活是肿瘤发生的重要表观遗传学特征之一。然而，很少有研究系统地确定了在癌组织中特异性的增强子。MethodsHere，我们研究了组蛋白修饰在MMTV-PyVT乳腺癌模型中的变化，结合基于质谱的蛋白质组学和基于ChIP-seq的表观基因组学方法。部分蛋白质组学结果用免疫印迹和免疫组化染色进行了验证。结果H3 K27 ac和H4 K8 ac在肿瘤组织中表达升高，并在患者组织芯片中得到证实。ChIP-seq显示H4 K8 ac与H3 K27 ac共定位于染色质上，尤其是在远端增强子上。表观基因组学研究进一步鉴定了在基因间区域中由H3 K4 me 3峰标记的超级增强子亚组。与常规超级增强子的平均水平相比，H3 K4 me 3富集区域增强子与更高水平的H3 K27 ac和H4 K8 ac相关，并且与其相邻基因的更高转录水平相关。我们鉴定了148个富含H3 K4 me 3的超级增强子，它们在肿瘤中具有更高的基因表达，这可能对乳腺癌至关重要。一种p300和H3 K27 ac的抑制剂，C646，抑制肿瘤的形成可能通过抑制Vegfa和其他genes. ConclusionsTogether，我们的工作确定了新的调节剂，并提供了重要的资源，在乳腺癌的全基因组增强子的研究，并提出了癌症治疗的可能性，通过调节增强子的活性。
BackgroundActivation of transcription enhancers, especially super-enhancers, is one of the critical epigenetic features of tumorigenesis. However, very few studies have systematically identified the enhancers specific in cancer tissues.MethodsHere, we studied the change of histone modifications in MMTV-PyVT breast cancer model, combining mass spectrometry-based proteomics and ChIP-seq-based epigenomics approaches. Some of the proteomic results were confirmed with western blotting and IHC staining. An inhibitor of H3K27ac was applied to study its effect on cancer development.ResultsH3K27ac and H4K8ac are elevated in cancer, which was confirmed in patient tissue chips. ChIP-seq revealed that H4K8ac is co-localized with H3K27ac on chromatin, especially on distal enhancers. Epigenomic studies further identified a subgroup of super-enhancers marked by H3K4me3 peaks in the intergenic regions. The H3K4me3-enriched regions enhancers are associated with higher level of H3K27ac and H4K8ac compared with the average level of conventional super-enhancers and are associated with higher transcription level of their adjacent genes. We identified 148 H3K4me3-enriched super-enhancers with higher gene expression in tumor, which may be critical for breast cancer. One inhibitor for p300 and H3K27ac, C646, repressed tumor formation probably through inhibiting Vegfa and other genes.ConclusionsTaken together, our work identifies novel regulators and provides important resource to the genome-wide enhancer studies in breast cancer and raises the possibility of cancer treatment through modulating enhancer activity.