A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks.
A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks.
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对肺腺癌表观基因组异质性的系统剖析揭示了两个具有不同预后和核心调控网络的不同亚类。
DOI：
10.1186/s13059-021-02376-1
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发表时间：
2021-05-17
期刊：
影响因子：
12.3
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Yuan C;Chen H;Tu S;Huang HY;Pan Y;Gui X;Kuang M;Shen X;Zheng Q;Zhang Y;Cheng C;Hong H;Tao X;Peng Y;Yao X;Meng F;Ji H;Shao Z;Sun Y
背景肺腺癌（LUAD）是一种高度恶性的异质性肿瘤，涉及多种致癌基因的改变。表观遗传过程在肺癌的发展中起着重要作用。然而，LUAD患者的增强子和超级增强子景观的变化在很大程度上仍然未知。为了深入了解LUAD的表观基因组异质性，我们研究了42例LUAD患者的肿瘤和邻近正常肺组织的H3 K27 ac组蛋白修饰概况，并探讨了表观遗传改变在LUAD progression.ResultsA高肿瘤间表观遗传异质性的作用。我们对近端基因启动子和远端增强子的H3 K27 ac水平的肿瘤间变异性进行了定量建模，并提出了LUAD患者的新表观遗传分类。我们的分类定义了两个与组织学亚型高度相关的LUAD亚组。II组患者的预后明显差于I组，这在公开的TCGA-LUAD队列中得到了进一步证实。组I和组II组之间的差异RNA-seq分析揭示，在组II组中上调的那些基因倾向于促进细胞增殖并诱导细胞去分化。我们构建了基因共表达网络，并确定了组特异性的核心调控因子。这些核心调控因子中的大多数与组特异性调控元件（例如超级增强子）连接。我们进一步表明，CLU是由3组I-特异性的核心调节和工程作为一种新的肿瘤抑制LUAD.ConclusionsOur研究系统的特点LUAD进展过程中的表观遗传学改变，并提供了一个新的分类模型，有助于预测患者的预后。
BackgroundLung adenocarcinoma (LUAD) is a highly malignant and heterogeneous tumor that involves various oncogenic genetic alterations. Epigenetic processes play important roles in lung cancer development. However, the variation in enhancer and super-enhancer landscapes of LUAD patients remains largely unknown. To provide an in-depth understanding of the epigenomic heterogeneity of LUAD, we investigate the H3K27ac histone modification profiles of tumors and adjacent normal lung tissues from 42 LUAD patients and explore the role of epigenetic alterations in LUAD progression.ResultsA high intertumoral epigenetic heterogeneity is observed across the LUAD H3K27ac profiles. We quantitatively model the intertumoral variability of H3K27ac levels at proximal gene promoters and distal enhancers and propose a new epigenetic classification of LUAD patients. Our classification defines two LUAD subgroups which are highly related to histological subtypes. Group II patients have significantly worse prognosis than group I, which is further confirmed in the public TCGA-LUAD cohort. Differential RNA-seq analysis between group I and group II groups reveals that those genes upregulated in group II group tend to promote cell proliferation and induce cell de-differentiation. We construct the gene co-expression networks and identify group-specific core regulators. Most of these core regulators are linked with group-specific regulatory elements, such as super-enhancers. We further show that CLU is regulated by 3 group I-specific core regulators and works as a novel tumor suppressor in LUAD.ConclusionsOur study systematically characterizes the epigenetic alterations during LUAD progression and provides a new classification model that is helpful for predicting patient prognosis.
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