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Author Notes:

To whom correspondence should be addressed: P. Vertino, Dept. of Radiation Oncology and the Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Rd., N.E., Rm. 4086, Atlanta, GA 30322. Tel.: 404-778-3119; Fax: 404-778-5530; E-mail: pvertin@emory.edu.

We thank Drs. Edwin Smith and John Lucchessi for antibodies against hMOF and hMSL1, Dr. Judd Rice for the pSUPERIOR.retro.puro vectors, and Dr. Or Gozani for advice regarding the peptide pulldown experiments.

Subjects:

Research Funding:

This work was supported, in whole or in part, by National Institute of Health Grants 2R01-CA077337 and 5R01-CA132065 (to P. M. V.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Chromatin Histone Modification
  • Chromatin Structure
  • Gene Regulation
  • RNA Polymerase
  • Transcription Regulation
  • H4K20me1
  • MSL Complex
  • PR-SET7
  • SETD8
  • RNA Polymerase II Promoter-proximal Pausing
  • SUV420H2
  • BROMODOMAIN PROTEIN BRD4
  • P-TEFB
  • S-PHASE
  • TRANSCRIPTION ELONGATION
  • DOSAGE COMPENSATION
  • DNA METHYLATION
  • MSL COMPLEX
  • DEPENDENT TRANSCRIPTION
  • DROSOPHILA-MELANOGASTER
  • PRODUCTIVE ELONGATION

A Dual Role for the Histone Methyltransferase PR-SET7/SETD8 and Histone H4 Lysine 20 Monomethylation in the Local Regulation of RNA Polymerase II Pausing

Tools:

Journal Title:

Journal of Biological Chemistry

Volume:

Volume 289, Number 11

Publisher:

, Pages 7425-7437

Type of Work:

Article | Final Publisher PDF

Abstract:

RNA polymerase II (Pol II) promoter-proximal pausing plays a critical role in postinitiation transcriptional regulation at many metazoan genes. We showed recently that histone H4 lysine 16 acetylation (H4K16Ac), mediated by the MSL complex, facilitates the release of paused Pol II. In contrast, H4 lysine 20 trimethylation (H4K20me3), mediated by SUV420H2, enforces Pol II pausing by inhibiting MSL recruitment. However, how the balance between H4K16Ac and H4K20me3 is locally regulated remains unclear. Here, we demonstrate that PR-SET7/SETD8, which monomethylates histone H4 lysine 20 (H4K20me1), controls both H4K16Ac and H4K20me3 and in doing so, regulates Pol II pausing dynamics. We find that PR-SET7-mediated H4K20me1 is necessary for the recruitment of the MSL complex, subsequent H4K16Ac, and release of Pol II into active elongation. Although dispensable for SUV420H2 recruitment, PR-SET7-mediated H4K20me1 is required for H4K20me3. Although depletion of SUV420H2 is sufficient to deplete H4K20me3 and relieve an H4K20me3-induced pause, pausing is maintained in the absence of PR-SET7 despite H4K20me3 depletion because of an inability to recruit the MSL complex in the absence of H4K20me1. These findings highlight the requirement for PR-SET7 and H4K20me1 in establishing both the H4K16Ac and H4K20me3 marks and point to a dual role in the local regulation of Pol II pausing.

Copyright information:

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

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