HBx induces hypomethylation of distal intragenic CpG islands required for active expression of developmental regulators

Sun Min Lee, Young Gun Lee, Jae Bum Bae, Jung Kyoon Choi, Chiharu Tayama, Kenichiro Hata, Yungdae Yun, Je Kyung Seong, Young Joon Kim

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Epigenetic alterations caused by viral oncoproteins are strong initiation factors for cancer development, but their mechanisms are largely unknown. To identify the epigenetic effects of viral hepatitis B virus X (HBx) that lead to hepatocellular carcinoma (HCC), we profiled the DNA methylomes of normal and HBx transgenic mouse liver. Intriguingly, severe hypomethylation of intragenic CpG islands (CGIs) was observed in HBx liver before the full development of HCC. Normally, these CGIs were highlymethylated (mCGIs) by the DNMT3L complex and marked with epigenetic signatures associated with active expression, such as H3K36me3. Hypomethylation of mCGI was caused by the downregulation of Dnmt3L and Dnmt3a due to HBx bound to their promoters, along with HDAC1. These events lead to the downregulation of many developmental regulators that could facilitate tumorigenesis. Here we provide an intriguing epigenetic regulation mediated by mCGI that is required for cell differentiation and describe a previously unidentified epigenetic role for HBx in promoting HCC development.

Original languageEnglish
Pages (from-to)9555-9560
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number26
DOIs
Publication statusPublished - 2014 Jul 1

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CpG Islands
Hepatitis B virus
Epigenomics
Hepatocellular Carcinoma
Down-Regulation
Peptide Initiation Factors
Liver
Oncogene Proteins
Transgenic Mice
Cell Differentiation
Carcinogenesis
DNA
Neoplasms

All Science Journal Classification (ASJC) codes

  • General

Cite this

Lee, Sun Min ; Lee, Young Gun ; Bae, Jae Bum ; Choi, Jung Kyoon ; Tayama, Chiharu ; Hata, Kenichiro ; Yun, Yungdae ; Seong, Je Kyung ; Kim, Young Joon. / HBx induces hypomethylation of distal intragenic CpG islands required for active expression of developmental regulators. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 26. pp. 9555-9560.
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HBx induces hypomethylation of distal intragenic CpG islands required for active expression of developmental regulators. / Lee, Sun Min; Lee, Young Gun; Bae, Jae Bum; Choi, Jung Kyoon; Tayama, Chiharu; Hata, Kenichiro; Yun, Yungdae; Seong, Je Kyung; Kim, Young Joon.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 26, 01.07.2014, p. 9555-9560.

Research output: Contribution to journalArticle

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AU - Choi, Jung Kyoon

AU - Tayama, Chiharu

AU - Hata, Kenichiro

AU - Yun, Yungdae

AU - Seong, Je Kyung

AU - Kim, Young Joon

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N2 - Epigenetic alterations caused by viral oncoproteins are strong initiation factors for cancer development, but their mechanisms are largely unknown. To identify the epigenetic effects of viral hepatitis B virus X (HBx) that lead to hepatocellular carcinoma (HCC), we profiled the DNA methylomes of normal and HBx transgenic mouse liver. Intriguingly, severe hypomethylation of intragenic CpG islands (CGIs) was observed in HBx liver before the full development of HCC. Normally, these CGIs were highlymethylated (mCGIs) by the DNMT3L complex and marked with epigenetic signatures associated with active expression, such as H3K36me3. Hypomethylation of mCGI was caused by the downregulation of Dnmt3L and Dnmt3a due to HBx bound to their promoters, along with HDAC1. These events lead to the downregulation of many developmental regulators that could facilitate tumorigenesis. Here we provide an intriguing epigenetic regulation mediated by mCGI that is required for cell differentiation and describe a previously unidentified epigenetic role for HBx in promoting HCC development.

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