Unraveling the key role of chromatin structure in cancer development through epigenetic landscape characterization of oral cancer

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yue Xue, Lu Liu, Ye Zhang, Yueying He, Jingyao Wang, Zicheng Ma, Tie-jun Li, Jianyun Zhang, Yanyi Huang, Yi Qin Gao
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引用次数: 0

Abstract

Epigenetic alterations, such as those in chromatin structure and DNA methylation, have been extensively studied in a number of tumor types. But oral cancer, particularly oral adenocarcinoma, has received far less attention. Here, we combined laser-capture microdissection and muti-omics mini-bulk sequencing to systematically characterize the epigenetic landscape of oral cancer, including chromatin architecture, DNA methylation, H3K27me3 modification, and gene expression. In carcinogenesis, tumor cells exhibit reorganized chromatin spatial structures, including compromised compartment structures and altered gene-gene interaction networks. Notably, some structural alterations are observed in phenotypically non-malignant paracancerous but not in normal cells. We developed transformer models to identify the cancer propensity of individual genome loci, thereby determining the carcinogenic status of each sample. Insights into cancer epigenetic landscapes provide evidence that chromatin reorganization is an important hallmark of oral cancer progression, which is also linked with genomic alterations and DNA methylation reprogramming. In particular, regions of frequent copy number alternations in cancer cells are associated with strong spatial insulation in both cancer and normal samples. Aberrant methylation reprogramming in oral squamous cell carcinomas is closely related to chromatin structure and H3K27me3 signals, which are further influenced by intrinsic sequence properties. Our findings indicate that structural changes are both significant and conserved in two distinct types of oral cancer, closely linked to transcriptomic alterations and cancer development. Notably, the structural changes remain markedly evident in oral adenocarcinoma despite the considerably lower incidence of genomic copy number alterations and lesser extent of methylation alterations compared to squamous cell carcinoma. We expect that the comprehensive analysis of epigenetic reprogramming of different types and subtypes of primary oral tumors can provide additional guidance to the design of novel detection and therapy for oral cancer.
通过对口腔癌的表观遗传景观特征分析,揭示染色质结构在癌症发展中的关键作用
表观遗传学改变,如染色质结构和 DNA 甲基化的改变,已在许多肿瘤类型中得到广泛研究。但口腔癌,尤其是口腔腺癌,受到的关注要少得多。在这里,我们结合激光捕获显微切割技术和突变组学微型批量测序技术,系统地描述了口腔癌的表观遗传学特征,包括染色质结构、DNA甲基化、H3K27me3修饰和基因表达。在癌变过程中,肿瘤细胞表现出染色质空间结构的重组,包括受损的区室结构和改变的基因-基因相互作用网络。值得注意的是,在表型为非恶性的癌旁细胞中观察到一些结构改变,而在正常细胞中则没有。我们开发了转化器模型来识别单个基因组位点的癌症倾向,从而确定每个样本的致癌状态。对癌症表观遗传景观的深入研究证明,染色质重组是口腔癌进展的一个重要标志,它还与基因组改变和DNA甲基化重编程有关。特别是,癌细胞中频繁发生拷贝数交替的区域与癌症和正常样本中强烈的空间隔离有关。口腔鳞状细胞癌中的异常甲基化重编程与染色质结构和 H3K27me3 信号密切相关,而染色质结构和 H3K27me3 信号又受到内在序列特性的影响。我们的研究结果表明,在两种不同类型的口腔癌中,结构变化既显著又保守,与转录组改变和癌症发展密切相关。值得注意的是,尽管与鳞状细胞癌相比,口腔腺癌的基因组拷贝数改变发生率低得多,甲基化改变程度也较低,但结构改变在口腔腺癌中仍然非常明显。我们期望,对不同类型和亚型的原发性口腔肿瘤的表观遗传学重编程进行全面分析,能为设计新型口腔癌检测和治疗方法提供更多指导。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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