Our studies have focused on the characterization of the molecular functions and biochemical properties of the Set1/MLL family of proteins and how their chimeras and mutations are associated with childhood leukemia and other forms of cancer. We have also focused on the role of chromatin and transcriptional elongation machinery in the regulation of developmental gene expression and how the misregulation of their activities is associated with malignancies. Our hope is that our molecular studies will advance our understanding of the molecular mechanisms of rearrangement-based and mutation-based cancer through the epigenetic regulators. Our biochemical and molecular studies demonstrated that Set1 in yeast exists in the Set1/COMPASS complex capable of methylating lysine 4 of histone H3 (H3K4). We demonstrated that Drosophila cells possess three Set1-related proteins and mammalian cells have six Set1-related proteins all found within COMPASS-like compositions capable of methylating histone H3K4. Furthermore, given that there is almost no sequence homology between many of the MLL translocation partners, for many years, it was unclear why MLL translocations into so many unrelated genes result in the pathogenesis of leukemia. Our biochemical studies on the purification of the MLL-chimeras demonstrated that many of the MLL translocation partners are part of the same macromolecular complex we named the Super Elongation Complex (SEC). We demonstrated that the translocations of MLL within any of the subunits of SEC subunits result in the misrecruitment of SEC to the MLL target genes and in the perturbation of the transcriptional checkpoint control of these genes, triggering leukemic growth. Additionally, the recent cataloging of somatic mutations in cancer identified a large number of mutations in the components of the MLL1-4 and Set1A/B complexes in both hematological malignancies and solid tumors. However, we know very little why the COMPASS family is mutated in different cancers. Given that we have developed a fantastic set of reagents and tools over the past seventeen years towards these factors and their associated proteins, chromatin, and other chromatin modifiers in multiple model systems; my laboratory is in a very unique position to define the molecular bases of these factors' involvement in cancer pathogenesis for the purpose of targeted therapeutics. Therefore, the goals of this R35 application is the full molecular and biochemical characterization of the COMPASS family, the translocation partners within the Super Elongation Complex (SEC), and the role of chromatin itself in the regulation of gene expression and development, and how their mutations contribute to the pathogenesis of human cancer.

Public Health Relevance

The focus of this R35 application is on the role of mutations of the chromatin and chromatin's modifying machineries in human malignancies. These factors have been demonstrated to be involved in different forms of cancers. Therefore, a better understanding of their molecular function is central to development of targeted therapeutics of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA197569-03
Application #
9312271
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Mietz, Judy
Project Start
2015-08-13
Project End
2022-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Hu, Deqing; Gao, Xin; Cao, Kaixiang et al. (2017) Not All H3K4 Methylations Are Created Equal: Mll2/COMPASS Dependency in Primordial Germ Cell Specification. Mol Cell 65:460-475.e6
Cao, Kaixiang; Collings, Clayton K; Marshall, Stacy A et al. (2017) SET1A/COMPASS and shadow enhancers in the regulation of homeotic gene expression. Genes Dev 31:787-801
Liang, Kaiwei; Volk, Andrew G; Haug, Jeffrey S et al. (2017) Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia. Cell 168:59-72.e13
Rickels, Ryan; Herz, Hans-Martin; Sze, Christie C et al. (2017) Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability. Nat Genet 49:1647-1653
Piunti, Andrea; Hashizume, Rintaro; Morgan, Marc A et al. (2017) Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas. Nat Med 23:493-500
Morgan, Marc A J; Rickels, Ryan A; Collings, Clayton K et al. (2017) A cryptic Tudor domain links BRWD2/PHIP to COMPASS-mediated histone H3K4 methylation. Genes Dev 31:2003-2014
Wang, Lu; Collings, Clayton K; Zhao, Zibo et al. (2017) A cytoplasmic COMPASS is necessary for cell survival and triple-negative breast cancer pathogenesis by regulating metabolism. Genes Dev 31:2056-2066
Sze, Christie C; Cao, Kaixiang; Collings, Clayton K et al. (2017) Histone H3K4 methylation-dependent and -independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation. Genes Dev 31:1732-1737
Rickels, Ryan; Hu, Deqing; Collings, Clayton K et al. (2016) An Evolutionary Conserved Epigenetic Mark of Polycomb Response Elements Implemented by Trx/MLL/COMPASS. Mol Cell 63:318-328
Piunti, Andrea; Shilatifard, Ali (2016) Epigenetic balance of gene expression by Polycomb and COMPASS families. Science 352:aad9780

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