The Histone Acetyl-Transferase MOZ Cooperates with the Histone Methyl-Transferase MLL to Regulate HOX Gene Expression in Human Hematopoietic Stem Cells

Abstract

MOZ (MOnocytic leukaemia Zinc finger protein) (also called MYST3 or KAT6A) is a member of the MYST family of HATs which likely acetylate H4K16. The MLL (MixedLineageLeukemia) gene is a frequent target for recurrent chromosomal translocations found in AML and ALL. MLL (KMT2A) is a methyl-transferase targeting H3K4. It was shown that MOZ/CBP leukemia, as observed in MLL-rearranged leukemias, harbors abnormal levels of homeobox (HOX) genes expression. HOX transcription factors have a crucial function in hematopoiesis regulation. In addition, HOXA5, HOXA7, and HOXA9 are often considered to be pivotal HOX genes for MLL transformation, constituting downstream targets of MLL. In our study, we characterize an in vivo cooperation between MOZ and MLL. MOZ co-localizes and interacts with MLL in vivo. We also demonstrate that WDR5, an adaptor protein essential for trimethylation of H3K4, belonging to the MLL complex, co-localizes and interacts with MOZ. Moreover, by in vitro pull-down assays, we show that MOZ can interact with the lysine 4 of histone H3 methylated by MLL, as WDR5. Hence, MLL, WDR5 and MOZ cooperate together on the same targets corresponding to the trimethylated H3K4. MOZ may couple histone acetylation to histone methylation throughout its recruitment on lysine methylated by MLL. Furthermore, ChIP experiments in HSCs indicate that MLL and MOZ are both recruited to HOXA5, HOXA7, and HOXA9 genes promoters in correlation with the presence of H3K9K14ac, H4K16ac, H3K4me2 and H3K4me3, specific epigenetic marks of transcription activation. Remarkably, knockdown of MLL or MOZ inhibits MOZ or MLL recruitment and their specific epigenetic marks from HOX genes promoters, respectively. These alterations are associated with abnormalities in hematopoietic differentiation of HSCs. Our data suggest that the histone methyl-transferase MLL and the MYST family histone acetyl-transferase MOZ functionally cooperate to modulate HOX genes expression through specific epigenetic modifications in HSCs. In conclusion, we provide an example of a mechanism involving a direct cross-talk between two histone modifying enzymes, facilitating the rapid remodeling of chromatin in order to favor the commitment of human HSCs via HOX genes regulation.