Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

Abstract

MOZ and MLL, encoding a histone acetyltransferase (HAT) and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. In MOZ (MOnocytic leukemia Zinc-finger protein)/CBP-or mixed lineage leukemia (MLL)-rearranged leukemias, abnormal levels of HOX transcription factors have been found to be critical for leukemogenesis. We show that MOZ and MLL cooperate to regulate these key genes in human cord blood CD34 þ cells. These chromatinmodifying enzymes interact, colocalize and functionally cooperate, and both are recruited to multiple HOX promoters. We also found that WDR5, an adaptor protein essential for lysine 4 trimethylation of histone H3 (H3K4me3) by MLL, colocalizes and interacts with MOZ. We detected the binding of the HAT MOZ to H3K4me3, thus linking histone methylation to acetylation. In CD34 þ cells, depletion of MLL causes release of MOZ from HOX promoters, which is correlated to defective histone activation marks, leading to repression of HOX gene expression and alteration of commitment of CD34 þ cells into myeloid progenitors. Thus, our results unveil the role of the interaction between MOZ and MLL in CD34 þ cells in which both proteins have a critical role in hematopoietic cell-fate decision, suggesting a new molecular mechanism by which MOZ or MLL deregulation leads to leukemogenesis.

Combinatorial readout of unmodified H3R2 and acetylated H3K14 by the tandem PHD finger of MOZ reveals a regulatory mechanism for HOXA9 transcription

“…7C). Supportive of these findings, another study showed that MOZ and MLL, an H3K4me2/3 HMT complex, interact, colocalize, and functionally cooperate on multiple HOX promoters (Paggetti et al 2010), highlighting the relationships between MOZ and the modifications of H3K4me3 and H3K14ac.…”

“…Moreover, one recent study in HEK293T and CD44 + cells has demonstrated the binding of MOZ to the HOXA9 gene promoter (Paggetti et al 2010). In light of our findings that the tandem PHD finger of MOZ could interact with the histone H3 tail, an interesting question emerges as to whether this binding contributes to a gene-specific targeting.…”

Recognition of Unmodified Histone H3 by the First PHD Finger of Bromodomain-PHD Finger Protein 2 Provides Insights into the Regulation of Histone Acetyltransferases Monocytic Leukemic Zinc-finger Protein (MOZ) and MOZ-related factor (MORF)

“…S10) (46). Interestingly, MOZ itself is also able to bind H3K4me3 (47). The presence of multiple histone binding domains in a single complex raises the following questions.…”

The histone methyltransferase activity of mll1 is dispensable for hematopoiesis and leukemogenesis

“…MLL1 interacts physically and/or genetically with p300/CBP, MOF, and MOZ histone acetyltransferases (Dou et al, 2005;Ernst et al, 2001;Paggetti et al, 2010). Although the CBP/p300-mediated H3K27Ac and MOZ-mediated H3K9Ac modifications were stable throughout the time course ( Figures S4E, S5A, and S5B), H4K16Ac was rapidly reduced around the TSS of MLL1 target genes in Mll1 Δ/Δ cells ( Figure 5A) as was MOF itself ( Figure 5B).…”