The interaction of MYC with the trithorax protein ASH2L promotes gene transcription by regulating H3K27 modification

Abstract

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.

Menin enhances c-Myc-mediated transcription to promote cancer progression

“…However, recent evidence suggest that these MLL cofactors might have broader effects than serving as HMTs. Ullius et al 60. reported recently that ASH2L, an MLL subunit, interacts directly with the bHLHZ domain of MYC and promotes gene transcription by modifying H2K27 acetylation.…”

Interaction with WDR5 Promotes Target Gene Recognition and Tumorigenesis by MYC

“…Consistent with identification of WDR5 via a two-hybrid assay, we also determined that interaction between the two proteins is direct, as recombinant full-length MYC and WDR5 interact when expressed and purified from Escherichia coli (Figure 1E). WDR5 has also been identified as a MYC-binding partner by Ullius et al, (2014), and was detected in a recent proteomic survey for MYC-interacting proteins (Dingar et al, 2014). Together, these data establish that WDR5 is a bona-fide and direct interaction partner that associates with the central portion of MYC.…”

MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

“…6C). Alternatively, MYC has been shown to bind at least two of the core subunits of KMT2 methyltransferase complexes that target histone H3 lysine 4, a mark associated with open chromatin (60). Interestingly, one of these subunits, WDR5, has recently been shown to bind several lncRNAs through an RNA binding pocket essential for its function as a transcriptional activator (61).…”