The MOZ Histone Acetyltransferase in Epigenetic Signaling and Disease

Abstract

The monocytic leukemic zinc finger (MOZ) histone acetyltransferase (HAT) plays a role in acute myeloid leukemia (AML). It functions as a quaternary complex with the bromodomain PHD finger protein 1 (BRPF1), the human Esa1-associated factor 6 homolog (hEAF6), and the inhibitor of growth 5 (ING5). Each of these subunits contain chromatin reader domains that recognize specific post-translational modifications (PTMs) on histone tails, and this recognition directs the MOZ HAT complex to specific chromatin substrates. The structure and function of these epigenetic reader modules has now been elucidated, and a model describing how the cooperative activity of these domains regulates HAT activity in response to the epigenetic landscape is proposed. The emerging role of epigenetic reader domains in disease, and their therapeutic potential for many types of cancer is also highlighted.

Emerging therapeutic targets in human acute myeloid leukemia (part 2) – bromodomain inhibition should be considered as a possible strategy for various patient subsets

“…MOZ has been identified as a fusion partner to various transcriptional regulators in several other genetic abnormalities [46,47]; these observations suggest that the MOZ-HAT tetraheterodimer and thereby the bromodomain-containing BRPF1 protein contributes to leukemic transformation also in these AML variants. One of these abnormalities is the inv(8) that causes a fusion between the MOZ-HAT and the TIF2 genes [48], and the encoded fusion protein forms a stable complex with the bromodomain-containing and histone-recognizing BRPF1 of the tetraheteromer.…”

“…In this abnormality, MOZ forms a fusion gene with the p300 histone acetyl transferase; the MOZ acetyltransferase domain is intact, and aberrant acetyl transferase activity may thus be important for leukemogenesis also in this AML variant [46].…”

“…All these observations suggest that BRD4 inhibition either as monotherapy or in combination with conventional or new targeted therapy should be further investigated in human AML. New BRD4 inhibitors are being developed, and these agents show high affinity and strong antiproliferative effects on the MV4-11 AML cell line [43], but at present it is not possible to decide which inhibitor should be preferred with regard to The BET family in AML with chromosome 8 abnormalities The monocytic leukemic zinc-finger (MOZ) histone acetyltransferase (HAT) forms a heterotetradimer with the bromodomain plant homeodomain (PHD) finger protein 1 BRPF1, the human Esa-1-associated factor 6 and the inhibitor of growth 5 [46]. The bromodomain-containing BRPF1 is an important regulator of MOZ-HAT activity.…”

Heterogeneity in cancer stem cells

“…In melanoma, H3K4 demethylase JARID1B could be used as a biomarker to isolate a subpopulation of slowcycling melanoma cells [30]. MOZ (monocytic leukemic zinc finger) histone acetyltransferase in AML is associated with poor prognosis [31]. The non-coding RNAs, for instance, the microRNAs (miRNAs), also play crucial roles in epigenetic heterogeneity in CSCs.…”

Methyllysine Recognition by the Royal Family Modules: Chromo, Tudor, MBT, Chromo Barrel, and PWWP Domains

“…BRPF1 is a component of the MOZ (monocytic leukemia zinc finger) histone acetyltransferase complex that stimulates this enzymatic activity on nucleosomal histone H3 and free histones H3 and H4, and promotes transcription (Ullah et al 2008). It may be that recognition of a histone trimethyllysine by BRPF1-PWWP contributes to the recruitment of the MOZ complex to the appropriate sites for acetylation (Carlson and Glass 2014).…”