异常增强子低甲基化通过全局转录重编程促进肝癌发生。

StephenW

Nat Commun. 2019 Jan 18;10(1):335. doi: 10.1038/s41467-018-08245-z.
Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming.
Xiong L1,2, Wu F1,2, Wu Q2, Xu L2, Cheung OK2, Kang W1, Mok MT2, Szeto LLM2, Lun CY2, Lung RW1, Zhang J1, Yu KH1,3, Lee SD3, Huang G4, Wang CM4, Liu J4, Yu Z5, Yu DY6, Chou JL7, Huang WH7, Feng B2, Cheung YS8, Lai PB8, Tan P9,10, Wong N1, Chan MW7, Huang TH4, Yip KY11, Cheng AS12, To KF13,14.
Author information

1
    Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
2
    School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
3
    Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China.
4
    Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
5
    Department of Liver Disease, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
6
    Disease Model Research Laboratory, Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.
7
    Department of Biomedical Sciences, National Chung Cheng University, Chia-Yi 62102, Taiwan, Republic of China.
8
    Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China.
9
    Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore.
10
    Genome Institute of Singapore, Singapore 138672, Singapore.
11
    Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China. [email protected].
12
    School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. [email protected].
13
    Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China. [email protected].
14
    State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China. [email protected].

Abstract

Hepatocellular carcinomas (HCC) exhibit distinct promoter hypermethylation patterns, but the epigenetic regulation and function of transcriptional enhancers remain unclear. Here, our affinity- and bisulfite-based whole-genome sequencing analyses reveal global enhancer hypomethylation in human HCCs. Integrative epigenomic characterization further pinpoints a recurrent hypomethylated enhancer of CCAAT/enhancer-binding protein-beta (C/EBPβ) which correlates with C/EBPβ over-expression and poorer prognosis of patients. Demethylation of C/EBPβ enhancer reactivates a self-reinforcing enhancer-target loop via direct transcriptional up-regulation of enhancer RNA. Conversely, deletion of this enhancer via CRISPR/Cas9 reduces C/EBPβ expression and its genome-wide co-occupancy with BRD4 at H3K27ac-marked enhancers and super-enhancers, leading to drastic suppression of driver oncogenes and HCC tumorigenicity. Hepatitis B X protein transgenic mouse model of HCC recapitulates this paradigm, as C/ebpβ enhancer hypomethylation associates with oncogenic activation in early tumorigenesis. These results support a causal link between aberrant enhancer hypomethylation and C/EBPβ over-expression, thereby contributing to hepatocarcinogenesis through global transcriptional reprogramming.

PMID:
    30659195
DOI:
    10.1038/s41467-018-08245-z

StephenW

Nat Commun。 2019年1月18日; 10（1）：335。 doi：10.1038 / s41467-018-08245-z。
异常增强子低甲基化通过全局转录重编程促进肝癌发生。
熊L1,2，吴F1,2，吴Q2，徐L2，张OK 2，康W1，莫MT2，Szeto LLM2，伦CY2，龙RW1，张J1，于KH1,3，李SD3，黄G4，王CM4 ，Liu J4，Yu Z5，Yu DY6，Chou JL7，Huang WH7，Feng B2，Cheung YS8，Lai PB8，Tan P9,10，Wong N1，Chan MW7，Huang TH4，Yip KY11，Cheng AS12，To KF13,14。
作者信息

1
    香港中文大学解剖与细胞病理学系，中国香港特别行政区。
2
    香港中文大学生物医学科学学院，中国香港特别行政区。
3
    香港中文大学计算机科学与工程系，中国香港特别行政区。
4
    德克萨斯大学健康科学中心分子医学系，圣安东尼奥，圣安东尼奥，德克萨斯州78245，美国。
五
    上海中医药大学附属曙光医院肝病科，上海201203
6
    疾病模型研究实验室，韩国生物科学与生物技术研究所基因组编辑研究中心，大韩305-806。
7
    国立中正大学生物医学系，中华人民共和国台湾嘉义62102。
8
    香港中文大学外科，中国香港特别行政区。
9
    新加坡Duke-NUS医学院癌症和干细胞生物学专业，新加坡169857。
10
    新加坡基因组研究所，新加坡138672，新加坡。
11
    香港中文大学计算机科学与工程系，中国香港特别行政区。 [email protected]。
12
    香港中文大学生物医学科学学院，中国香港特别行政区。 [email protected]。
13
    香港中文大学解剖与细胞病理学系，中国香港特别行政区。 [email protected]。
14
    中国香港特别行政区中国大学转化肿瘤学国家重点实验室。 [email protected]。

抽象

肝细胞癌（HCC）表现出不同的启动子高甲基化模式，但转录增强子的表观遗传调节和功能仍不清楚。在这里，我们的基于亲和和亚硫酸氢盐的全基因组测序分析揭示了人类HCC中的全局增强子低甲基化。整合的表观基因组学表征进一步确定了CCAAT /增强子结合蛋白-β（C /EBPβ）的复发性低甲基化增强子，其与C /EBPβ过表达和患者的较差预后相关。 C /EBPβ增强子的去甲基化通过增强子RNA的直接转录上调重新激活自增强增强子 - 靶环。相反，通过CRISPR / Cas9缺失该增强子降低了C /EBPβ表达及其在H3K27ac标记的增强子和超增强子上与BRD4的全基因组共同占据，导致驱动癌基因和HCC致瘤性的显着抑制。 HCC的乙型肝炎X蛋白转基因小鼠模型概括了这种范例，因为C /ebpβ增强子低甲基化与早期肿瘤发生中的致癌活化相关。这些结果支持异常增强子低甲基化和C /EBPβ过表达之间的因果关系，从而通过全局转录重编程促进肝癌发生。

结论：
    30659195
DOI：
    10.1038 / s41467-018-08245-Z