This Article Full Text Full Text (PDF) Supplemental material Other Versions of this Article: MCB.00410-08v1 28/14/4459    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Sims, J. K. Articles by Rice, J. C. PubMed PubMed Citation Articles by Sims, J. K. Articles by Rice, J. C.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 2008, p. 4459-4468, Vol. 28, No. 14
0270-7306/08/$08.00+0     doi:10.1128/MCB.00410-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

PR-Set7 Establishes a Repressive trans-Tail Histone Code That Regulates Differentiation ^,

Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, California 90033

Received 11 March 2008/ Returned for modification 16 April 2008/ Accepted 1 May 2008

Posttranslational modifications of the DNA-associated histone proteins play fundamental roles in eukaryotic transcriptional regulation. We previously discovered a novel trans-tail histone code involving monomethylated histone H4 lysine 20 (H4K20) and H3 lysine 9 (H3K9); however, the mechanisms that establish this code and its function in transcription were unknown. In this report, we demonstrate that H3K9 monomethylation is dependent upon the PR-Set7 H4K20 monomethyltransferase but independent of its catalytic function, indicating that PR-Set7 recruits an H3K9 monomethyltransferase to establish the trans-tail histone code. We determined that this histone code is involved in a transcriptional regulatory pathway in vivo whereby monomethylated H4K20 binds the L3MBTL1 repressor protein to repress specific genes, including RUNX1, a critical regulator of hematopoietic differentiation. The selective loss of monomethylated H4K20 at the RUNX1 promoter resulted in the displacement of L3MBTL1 and a concomitant increase in RUNX1 transcription. Importantly, the lack of monomethylated H4K20 in the human K562 multipotent cell line was specifically associated with spontaneous megakaryocytic differentiation, in part, by activating RUNX1. Our findings demonstrate that this newly described repression pathway is required for regulating proper megakaryopoiesis and suggests that it is likely to function similarly in other multipotent cell types to regulate specific differentiation pathways.

Published ahead of print on 12 May 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.