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Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming.
Xiong, Lei; Wu, Feng; Wu, Qiong; Xu, Liangliang; Cheung, Otto K; Kang, Wei; Mok, Myth T; Szeto, Lemuel L M; Lun, Cheuk-Yin; Lung, Raymond W; Zhang, Jinglin; Yu, Ken H; Lee, Sau-Dan; Huang, Guangcun; Wang, Chiou-Miin; Liu, Joseph; Yu, Zhuo; Yu, Dae-Yeul; Chou, Jian-Liang; Huang, Wan-Hong; Feng, Bo; Cheung, Yue-Sun; Lai, Paul B; Tan, Patrick; Wong, Nathalie; Chan, Michael W; Huang, Tim H; Yip, Kevin Y; Cheng, Alfred S; To, Ka-Fai.
Afiliación
  • Xiong L; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Wu F; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Wu Q; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Xu L; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Cheung OK; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Kang W; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Mok MT; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Szeto LLM; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Lun CY; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Lung RW; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Zhang J; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Yu KH; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Lee SD; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Huang G; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Wang CM; Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Liu J; Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Yu Z; Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
  • Yu DY; Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
  • Chou JL; Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
  • Huang WH; Department of Liver Disease, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • Feng B; Disease Model Research Laboratory, Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.
  • Cheung YS; Department of Biomedical Sciences, National Chung Cheng University, Chia-Yi 62102, Taiwan, Republic of China.
  • Lai PB; Department of Biomedical Sciences, National Chung Cheng University, Chia-Yi 62102, Taiwan, Republic of China.
  • Tan P; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Wong N; Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Chan MW; Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Huang TH; Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore.
  • Yip KY; Genome Institute of Singapore, Singapore 138672, Singapore.
  • Cheng AS; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • To KF; Department of Biomedical Sciences, National Chung Cheng University, Chia-Yi 62102, Taiwan, Republic of China.
Nat Commun ; 10(1): 335, 2019 01 18.
Article en En | MEDLINE | ID: mdl-30659195
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/EBPß) which correlates with C/EBPß over-expression and poorer prognosis of patients. Demethylation of C/EBPß 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/EBPß 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/ebpß enhancer hypomethylation associates with oncogenic activation in early tumorigenesis. These results support a causal link between aberrant enhancer hypomethylation and C/EBPß over-expression, thereby contributing to hepatocarcinogenesis through global transcriptional reprogramming.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Secuencias Reguladoras de Ácidos Nucleicos / Metilación de ADN / Carcinogénesis / Neoplasias Hepáticas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2019 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Secuencias Reguladoras de Ácidos Nucleicos / Metilación de ADN / Carcinogénesis / Neoplasias Hepáticas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2019 Tipo del documento: Article País de afiliación: China