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Shilatifard and colleagues clarify the enzymatic activity of factors involved in childhood leukemia

May 05, 2009

The Stowers Institute's Shilatifard Lab and colleagues have provided new insight into the molecular basis for H3K4 methylation, an activity associated with the MLL protein found in chromosomal translocation-based aggressive infant acute leukemias. Studies describing these collaborative studies were published online by Molecular and Cellular Biology and Cell this week.

Many hematological malignancies are associated with a genetic error in which a portion of one chromosome has broken and fused with another chromosome. This inappropriate fusion of chromosomal DNA is referred to as chromosomal translocation. A large proportion of infant leukemias are the result of chromosomal translocations in the Mixed Lineage Leukemia (MLL) gene. Children suffering from these chromosomal translocations have low survival rates and face treatment options that have devastating side effects.

The Stowers Institute's Shilatifard Lab studies chromosomal translocations related to the MLL gene. Several years ago, they identified a molecular complex - COMPASS - containing the yeast homologue of the human MLL. COMPASS was the first H3K4 methylase to be identified, and human MLL is also found in COMPASS-like complexes capable of methylating H3K4, a posttranslational modification marking chromosomes for transcription.

"We observed that the addition of three methyl groups (a process known as trimethylation) on the fourth lysine of H3K4 is regulated by the active site of the yeast equivalent of the MLL protein complex, COMPASS," said Yoh-hei Takahashi, Ph.D., Postdoctoral Research Associate and first author on the publication in Molecular and Cellular Biology. "We also demonstrated that a single residue (Tyr1052) functions with a known subunit of COMPASS (Cps40) to regulate the trimethylation of H3K4."

"These are exciting findings because each of these are significant steps that lead to unraveling how translocations cause leukemia and how we can develop treatments that better target and cure leukemia," said Ali Shilatifard, Ph.D., Investigator and senior author on the publication.

Additional contributing authors to the study published in Molecular and Cellular Biology from the Stowers Institute include Jung Shin Lee, Ph.D., Postdoctoral Research Associate; Selene Swanson, Research Specialist II; Anita Saraf, M.D., Ph.D., Senior Proteomics Scientist; Laurence Florens, Ph.D., Managing Director of Proteomics; and Michael Washburn, Ph.D., Director of Proteomics Center. Raymond Trievel, Ph.D., of the University of Michigan also contributed.

The Shilatifard Lab also has collaborated with Robert Roeder and colleagues at The Rockefeller University on a publication in Cell that sheds new light on the process of communication between histones known as histone crosstalk. This process has been a topic of interest to the Shilatifard Lab for many years, and they have made a number of important contributions to its understanding.

Through a series of laborious biochemical and genetic screens in yeast and over five years of work, the Shilatifard Lab identified the molecular machinery required for proper H3K4 methylation by COMPASS. This includes the modification of histone H2B by attaching a single ubiquitin - a regulatory protein that is very similar from species to species - by the Rad6/Bre1 complex in a process called histone crosstalk. In the Cell publication, the team demonstrated that human Rad6/Bre1 also functions in histone crosstalk as it does in yeast.

"This study demonstrates the awesome power of simple genetic and biochemical model systems such as yeast in deciphering molecular machinery involved in chromatin biology and how yeast can play a role as a template in identifying the human counterparts of these proteins," said Dr. Shilatifard. "Indeed, as reported this week in Cell, human Rad6 can functionally replace yeast Rad6, and H2B monoubiquitination in humans functions by the same histone crosstalk mechanism as it does in yeast, demonstrating the conservation in this system from yeast to humans."

Stowers Institute for Medical Research