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Molecular and Cellular Biology, March 2007, p. 1889-1903, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01506-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Knockdown of ALR (MLL2) Reveals ALR Target Genes and Leads to Alterations in Cell Adhesion and Growth{triangledown} ,{dagger}

Irina Issaeva,1 Yulia Zonis,1 Tanya Rozovskaia,1 Kira Orlovsky,1 Carlo M. Croce,2 Tatsuya Nakamura,2 Alex Mazo,3 Lea Eisenbach,4 and Eli Canaani1*

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel,1 Institute of Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43221,2 Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107,3 Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel4

Received 13 August 2006/ Returned for modification 25 September 2006/ Accepted 30 November 2006

ALR (MLL2) is a member of the human MLL family, which belongs to a larger SET1 family of histone methyltransferases. We found that ALR is present within a stable multiprotein complex containing a cohort of proteins shared with other SET1 family complexes and several unique components, such as PTIP and the jumonji family member UTX. Like other complexes formed by SET1 family members, the ALR complex exhibited strong H3K4 methyltransferase activity, conferred by the ALR SET domain. By generating ALR knockdown cell lines and comparing their expression profiles to that of control cells, we identified a set of genes whose expression is activated by ALR. Some of these genes were identified by chromatin immunoprecipitation as direct ALR targets. The ALR complex was found to associate in an ALR-dependent fashion with promoters and transcription initiation sites of target genes and to induce H3K4 trimethylation. The most characteristic features of the ALR knockdown cells were changes in the dynamics and mode of cell spreading/polarization, reduced migration capacity, impaired anchorage-dependent and -independent growth, and decreased tumorigenicity in mice. Taken together, our results suggest that ALR is a transcriptional activator that induces the transcription of target genes by covalent histone modification. ALR appears to be involved in the regulation of adhesion-related cytoskeletal events, which might affect cell growth and survival.

* Corresponding author. Mailing address: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Phone: 972-8-9342292. Fax: 972-8-9344125. E-mail: eli.canaani{at}weizmann.ac.il.

{triangledown} Published ahead of print on 18 December 2006.

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

Molecular and Cellular Biology, March 2007, p. 1889-1903, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01506-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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