This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gregory, G. D.
Right arrow Articles by Blobel, G. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gregory, G. D.
Right arrow Articles by Blobel, G. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 2007, p. 8466-8479, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.00993-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mammalian ASH1L Is a Histone Methyltransferase That Occupies the Transcribed Region of Active Genes{triangledown} ,{dagger}

Gregory D. Gregory,1 Christopher R. Vakoc,1,2 Tanya Rozovskaia,3 Xingwu Zheng,1 Shetal Patel,1,2 Tatsuya Nakamura,4 Eli Canaani,3 and Gerd A. Blobel1,2*

The Children's Hospital of Philadelphia, Division of Hematology, Philadelphia, Pennsylvania 19104,1 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,2 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel,3 Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio 432104

Received 5 June 2007/ Returned for modification 21 July 2007/ Accepted 28 September 2007

Histone lysine methylation regulates genomic functions, including gene transcription. Previous reports found various degrees of methylation at H3K4, H3K9, and H4K20 within the transcribed region of active mammalian genes. To identify the enzymes responsible for placing these modifications, we examined ASH1L, the mammalian homolog of the Drosophila melanogaster Trithorax group (TrxG) protein Ash1. Drosophila Ash1 has been reported to methylate H3K4, H3K9, and H4K20 at its target sites. Here we demonstrate that mammalian ASH1L associates with the transcribed region of all active genes examined, including Hox genes. The distribution of ASH1L in transcribed chromatin strongly resembles that of methylated H3K4 but not that of H3K9 or H4K20. Accordingly, the SET domain of ASH1L methylates H3K4 in vitro, and knockdown of ASH1L expression reduced H3K4 trimethylation at HoxA10 in vivo. Notably, prior methylation at H3K9 reduced ASH1L-mediated methylation at H3K4, suggesting cross-regulation among these marks. Drosophila ash1 and trithorax interact genetically, and the mammalian TrxG protein MLL1 and ASH1L display highly similar distributions and substrate specificities. However, by using MLL null cell lines we found that their recruitments occur independently of each other. Collectively, our data suggest that ASH1L occupies most, if not all, active genes and methylates histone H3 in a nonredundant fashion at a subset of genes.

* Corresponding author. Mailing address: Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104. Phone: (215) 590-3988. Fax: (215) 590-4834. E-mail: blobel{at}email.chop.edu

{triangledown} Published ahead of print on 8 October 2007.

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

Molecular and Cellular Biology, December 2007, p. 8466-8479, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.00993-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wang, P., Lin, C., Smith, E. R., Guo, H., Sanderson, B. W., Wu, M., Gogol, M., Alexander, T., Seidel, C., Wiedemann, L. M., Ge, K., Krumlauf, R., Shilatifard, A. (2009). Global Analysis of H3K4 Methylation Defines MLL Family Member Targets and Points to a Role for MLL1-Mediated H3K4 Methylation in the Regulation of Transcriptional Initiation by RNA Polymerase II. Mol. Cell. Biol. 29: 6074-6085 [Abstract] [Full Text]  
  • McCrea, P. D., Gu, D., Balda, M. S. (2009). Junctional Music that the Nucleus Hears: Cell-Cell Contact Signaling and the Modulation of Gene Activity. Cold Spring Harb. Perspect. Biol. 1: a002923-a002923 [Abstract] [Full Text]  
  • Wang, H., Hays, N. P., Das, S. K., Craig, R. L., Chu, W. S., Sharma, N., Elbein, S. C. (2009). Phenotypic and Molecular Evaluation of a Chromosome 1q Region with Linkage and Association to Type 2 Diabetes in Humans. J. Clin. Endocrinol. Metab. 94: 1401-1408 [Abstract] [Full Text]  
  • Steger, D. J., Lefterova, M. I., Ying, L., Stonestrom, A. J., Schupp, M., Zhuo, D., Vakoc, A. L., Kim, J.-E., Chen, J., Lazar, M. A., Blobel, G. A., Vakoc, C. R. (2008). DOT1L/KMT4 Recruitment and H3K79 Methylation Are Ubiquitously Coupled with Gene Transcription in Mammalian Cells. Mol. Cell. Biol. 28: 2825-2839 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»