The interaction of MYC with the trithorax protein ASH2L promotes gene transcription by regulating H3K27 modification.
The appropriate expression of the roughly 30,000 human genes requires multiple layers of control. The oncoprotein MYC, a transcriptional regulator, contributes to many of the identified control mechanisms, including the regulation of chromatin, RNA polymerases, and RNA processing. Moreover, MYC recruits core histone-modifying enzymes to DNA. We identified an additional transcriptional cofactor complex that interacts with MYC and that is important for gene transcription. We found that the trithorax protein ASH2L and MYC interact directly in vitro and co-localize in cells and on chromatin. ASH2L is a core subunit of KMT2 methyltransferase complexes that target histone H3 lysine 4 (H3K4), a mark associated with open chromatin. Indeed, MYC associates with H3K4 methyltransferase activity, dependent on the presence of ASH2L. MYC does not regulate this methyltransferase activity but stimulates demethylation and subsequently acetylation of H3K27. KMT2 complexes have been reported to associate with histone H3K27-specific demethylases, while CBP/p300, which interact with MYC, acetylate H3K27. Finally WDR5, another core subunit of KMT2 complexes, also binds directly to MYC and in genome-wide analyses MYC and WDR5 are associated with transcribed promoters. Thus, our findings suggest that MYC and ASH2L-KMT2 complexes cooperate in gene transcription by controlling H3K27 modifications and thereby regulate bivalent chromatin.
Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany.
Andrea
A
Ullius
Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany.
Juliane
J
Lüscher-Firzlaff
IZKF Research Group Computational Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany.
Ivan G
IG
Costa
Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany.
Gesa
G
Walsemann
Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany.
Alexandra H
AH
Forst
IZKF Research Group Computational Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany.
Eduardo G
EG
Gusmao
Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany.
Karsten
K
Kapelle
Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany.
Henning
H
Kleine
Helmholtz Zentrum München, Institut für Molekulare Immunologie, Marchioninistr. 25, 81377 München, Germany.
Elisabeth
E
Kremmer
Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany jvervoorts-weber@ukaachen.de.
Jörg
J
Vervoorts
Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, 52074 Aachen, Germany Luescher@rwth-aachen.de.
Bernhard
B
Lüscher
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008745:Methylation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic
C485622:ASH2L protein, human; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C502547:WDR5 protein, human; D011495:Histone-Lysine N-Methyltransferase