How chromatin domains are established and maintained in higher eukaryotes are poorly understood, especially during development. Covalent modifications of histones carry significant amount of information that complement to genetic information in dictating developmental process. Mutations in histone modifying enzymes are commonly found in human diseases, further underlying their fundamental roles in cells. One such enzyme is MLL1 (mixed lineage leukemia), which is evolutionarily conserved and promotes 5'Hox gene transcription. MLL1 is a histone methyltransferase for H3 lysine 4, a mark highly enriched at gene promoters and enhancers. Studies have found that MLL1 plays important roles in normal and malignant hematopoiesis. Knockout MLL1 gene leads to profound defects in hematopoietic stem cells compartment and blocks MLL1 fusion protein mediated leukemogenesis. Despite these findings, the obligatory function of H3 K4 methylation in MLL1 dependent biological pathways remains unclear. Our biochemical studies have revealed that the MLL1 methyltransferase activity is tightly regulated by three proteins including WDR5, RbBP5 and ASH2L. We, and others, further demonstrate that MLL1-WDR5 interaction is essential for complex integrity. Blocking this interaction abolishes MLL1 activity. Based on these results, we have developed a highly specific chemical probe that targets MLL1 methyltransferase activity by disrupting MLL1 complex assembly. Using this novel probe, we will directly address the function of MLL1 mediated H3 K4 methylation in malignant process (without affecting other MLL1 functions). This novel probe also, for the first time, allows us to examine the dynamic and reversible functions of H3K4 methylation during normal cell differentiation. Our studies will have high impact in the chromatin field and translational research.

Public Health Relevance

Mixed lineage leukemia (MLL) is a form of cancer in which the normal development of blood cells is blocked and the cells abnormally proliferate. Mutations in MLL gene associate with ~10% AML and ALL cases in both children and adults. The goal of work is to understand the fundamental mechanism of MLL1-mediated transcription regulation and other cellular processes. Our studies will lay foundations for developing further therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM082856-06
Application #
8771708
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Carter, Anthony D
Project Start
2009-04-01
Project End
2018-02-28
Budget Start
2014-07-10
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
$319,133
Indirect Cost
$112,687
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Wu, Lipeng; Lee, Shirley Y; Zhou, Bo et al. (2013) ASH2L regulates ubiquitylation signaling to MLL: trans-regulation of H3 K4 methylation in higher eukaryotes. Mol Cell 49:1108-20
Cao, Fang; Chen, Yong; Cierpicki, Tomasz et al. (2010) An Ash2L/RbBP5 heterodimer stimulates the MLL1 methyltransferase activity through coordinated substrate interactions with the MLL1 SET domain. PLoS One 5:e14102
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