The histone H2B-specific ubiquitin ligase RNF20/hBRE1 acts as a putative tumor suppressor through selective regulation of gene expression

  1. Efrat Shema1,
  2. Itay Tirosh2,
  3. Yael Aylon1,
  4. Jing Huang3,
  5. Chaoyang Ye3,
  6. Neta Moskovits1,
  7. Nina Raver-Shapira1,
  8. Neri Minsky1,8,
  9. Judith Pirngruber4,
  10. Gabi Tarcic5,
  11. Pavla Hublarova6,
  12. Lilach Moyal7,
  13. Mali Gana-Weisz7,
  14. Yosef Shiloh7,
  15. Yossef Yarden5,
  16. Steven A. Johnsen4,
  17. Borivoj Vojtesek6,
  18. Shelley L. Berger3, and
  19. Moshe Oren1,9
  1. 1 Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel;
  2. 2 Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel;
  3. 3 Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA;
  4. 4 Department of Molecular Oncology, Gottingen Center for Molecular Biosciences, Gottingen 37077, Germany;
  5. 5 Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel;
  6. 6 Department of Oncological and Experimental Pathology, Masaryk Memorial Cancer Institute, 65653 Brno, Czech Republic;
  7. 7 Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

Abstract

Histone monoubiquitylation is implicated in critical regulatory processes. We explored the roles of histone H2B ubiquitylation in human cells by reducing the expression of hBRE1/RNF20, the major H2B-specific E3 ubiquitin ligase. While H2B ubiquitylation is broadly associated with transcribed genes, only a subset of genes was transcriptionally affected by RNF20 depletion and abrogation of H2B ubiquitylation. Gene expression dependent on RNF20 includes histones H2A and H2B and the p53 tumor suppressor. In contrast, RNF20 suppresses the expression of several proto-oncogenes, which reside preferentially in closed chromatin and are modestly transcribed despite bearing marks usually associated with high transcription rates. Remarkably, RNF20 depletion augmented the transcriptional effects of epidermal growth factor (EGF), increased cell migration, and elicited transformation and tumorigenesis. Furthermore, frequent RNF20 promoter hypermethylation was observed in tumors. RNF20 may thus be a putative tumor suppressor, acting through selective regulation of a distinct subset of genes.

Keywords

Footnotes

  • 8

    8 Present address: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10021, USA.

  • 9

    9 Corresponding author.

    9 E-MAIL moshe.oren{at}weizmann.ac.il; FAX 972-8-9346004.

  • Supplemental material is available at http://www.genesdev.org.

  • Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1703008.

    • Received June 6, 2008.
    • Accepted August 12, 2008.
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