MLL1 (mixed lineage leukemia) protein plays important roles in normal and malignant hematopoiesis by regulating the expression of a specific group of genes. It has been proposed that MLL1 affects gene expression through effecting histone H3 methylation on lysine 4, and through interactions with other chromatin modifying activities such histone acetyltransferases. The objectives of the proposed research are to understand the fundamental mechanisms of how MLL1 mediated transcription activation from compacted chromatin is achieved through concerted actions of different chromatin remodeling activities and to study the molecular basis for its well-described antagonism against Polycomb group proteins, which are critical components for epigenetic regulation of gene repression. The proposed research emphasizes on the regulation of MLL1 enzymatic activities in the complex, on the recruitment mechanism targeting MLL1 complex to promoters, and on downstream events that transduce the histone modifications to transcription activation, through the specific docking of downstream effectors. We will take clues from the structural analyses and the genomic mapping results of target genes, employ well-established methods such as MLL1 complex reconstitution and the recombinant chromatin-templated in vitro transcription assays for detailed mechanistic dissection of the series events leading to transcriptional activation. The in vitro studies will be complemented with in vivo approaches designed to guide and validate results obtained from cell-free system. The proposed work will significantly advance our knowledge for the functions of MLL1 in important processes such as embryonic development, hematopoiesis, cell fate determination and cell cycle control through transcriptional regulation of specific genes. Given that MLL1 mutations are commonly found in human myeloid and lymphoid acute leukemias, the proposed study also bears significance in elucidating mechanisms for leukemogenesis and thus, lays the foundation for advances in disease diagnosis, treatment, and prevention. This project matches best with the mission of national institute of general medical science (NIGMS) and is budgeted at $1,250,000 for a five-year period.

Public Health Relevance

Genetic changes of mixed lineage leukemia protein (MLL1) account for ~10% acute leukemia in adult and for ~70% infant leukemia in the population. The most notable signature for MLL-related leukemia is the change of specific gene expression pattern. This project is to understand the fundamental mechanism for these changes and thus, the cause of the disease. It will set up the foundation for potential medical interference in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM082856-05
Application #
8423748
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Carter, Anthony D
Project Start
2009-04-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$277,639
Indirect Cost
$97,938
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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Zhang, Hui; Gayen, Srimonta; Xiong, Jie et al. (2016) MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency. Cell Stem Cell 18:481-94
Xu, Jing; Li, Li; Xiong, Jie et al. (2016) MLL1 and MLL1 fusion proteins have distinct functions in regulating leukemic transcription program. Cell Discov 2:16008
Wang, Weimin; Kryczek, Ilona; Dostál, Lubomír et al. (2016) Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer. Cell 165:1092-105
Li, Yanjing; Han, Jianming; Zhang, Yuebin et al. (2016) Structural basis for activity regulation of MLL family methyltransferases. Nature 530:447-52
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Peng, Dongjun; Kryczek, Ilona; Nagarsheth, Nisha et al. (2015) Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527:249-53
Lee, Young-Tae; Gibbons, Garrett; Lee, Shirley Y et al. (2015) One-pot refolding of core histones from bacterial inclusion bodies allows rapid reconstitution of histone octamer. Protein Expr Purif 110:89-94
Su, Xiaonan; Zhu, Guixin; Ding, Xiaozhe et al. (2014) Molecular basis underlying histone H3 lysine-arginine methylation pattern readout by Spin/Ssty repeats of Spindlin1. Genes Dev 28:622-36
Wu, Lipeng; Li, Li; Zhou, Bo et al. (2014) H2B ubiquitylation promotes RNA Pol II processivity via PAF1 and pTEFb. Mol Cell 54:920-31

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