Browsing by Author "Ge, Kai"

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    H2B ubiquitylation enhances H3K4 methylation activities of human KMT2 family complexes
    (Oxford, 2020-06-04) Kwon, Minjung; Park, Kihyun; Hyun, Kwangbeom; Lee, Jeong-Heon; Zhou, Linjiao; Cho, Young-Wook; Ge, Kai; Skalnik, David G.; Muir, Tom W.; Kim, Jaehoon; Biology, School of Science
    In mammalian cells, distinct H3K4 methylation states are created by deposition of methyl groups by multiple complexes of histone lysine methyltransferase 2 (KMT2) family proteins. For comprehensive analyses that directly compare the catalytic properties of all six human KMT2 complexes, we employed a biochemically defined system reconstituted with recombinant KMT2 core complexes (KMT2CoreCs) containing minimal components required for nucleosomal H3K4 methylation activity. We found that each KMT2CoreC generates distinct states and different levels of H3K4 methylation, and except for MLL3 all are stimulated by H2Bub. Notably, SET1BCoreC exhibited the strongest H3K4 methylation activity and, to our surprise, did not require H2B ubiquitylation (H2Bub); in contrast, H2Bub was required for the H3K4me2/3 activity of the paralog SET1ACoreC. We also found that WDR5, RbBP5, ASH2L and DPY30 are required for efficient H3K4 methyltransferase activities of all KMT2CoreCs except MLL3, which could produce H3K4me1 in the absence of WDR5. Importantly, deletion of the PHD2 domain of CFP1 led to complete loss of the H3K4me2/3 activities of SET1A/BCoreCs in the presence of H2Bub, indicating a critical role for this domain in the H2Bub-stimulated H3K4 methylation. Collectively, our results suggest that each KMT2 complex methylates H3K4 through distinct mechanisms in which individual subunits differentially participate.
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    HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis
    (Elsevier, 2018-10-08) Sun, Yuqing; Zhou, Bo; Mao, Fengbiao; Xu, Jing; Miao, Hongzhi; Zou, Zhenhua; Khoa, Le Tran Phuc; Jang, Younghoon; Cai, Sheng; Witkin, Matthew; Koche, Richard; Ge, Kai; Dressler, Gregory; Levine, Ross L.; Armstrong, Scott A.; Dou, Yali; Hess, Jay L.; Pathology and Laboratory Medicine, School of Medicine
    Aberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program. We show that HOXA9 functions as a pioneer factor at de novo enhancers and recruits CEBPα and the MLL3/MLL4 complex. Genetic deletion of MLL3/MLL4 blocks histone H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo. These results suggest that therapeutic targeting of HOXA9-dependent enhancer reorganization can be an effective therapeutic strategy in acute leukemia with HOXA9 overexpression