The MOZ-BRPF1 acetyltransferase complex in epigenetic crosstalk linked to gene regulation, development, and human diseases

Abstract

Acetylation of lysine residues on histone tails is an important post-translational modification (PTM) that regulates chromatin dynamics to allow gene transcription as well as DNA replication and repair. Histone acetyltransferases (HATs) are often found in large multi-subunit complexes and can also modify specific lysine residues in non-histone substrates. Interestingly, the presence of various histone PTM recognizing domains (reader domains) in these complexes ensures their specific localization, enabling the epigenetic crosstalk and context-specific activity. In this review, we will cover the biochemical and functional properties of the MOZ-BRPF1 acetyltransferase complex, underlining its role in normal biological processes as well as in disease progression. We will discuss how epigenetic reader domains within the MOZ-BRPF1 complex affect its chromatin localization and the histone acetyltransferase specificity of the complex. We will also summarize how MOZ-BRPF1 is linked to development via controlling cell stemness and how mutations or changes in expression levels of MOZ/BRPF1 can lead to developmental disorders or cancer. As a last touch, we will review the latest drug candidates for these two proteins and discuss the therapeutic possibilities.

Keywords: BRPF1; KAT6A; MOZ; MYST acetyltransferase, MORF; cancer; development; epigenetics.

FIGURE 1

Multiple chromatin binding domains in the 4-subunit MOZ-BRPF1 complex inform about its biological properties and importance in transcription activation. (A) Protein domains of the MOZ-BRPF1 complex; MOZ, BRPF1, ING4/5 and MEAF6. Domains labelled as follows: NEMM, N-terminal part of Enok, MOZ and MORF; PHD, plant homeodomain-linked zinc finger; MYST, MYST histone acetyltransferase domain; Zn, zinc knuckle; I and II, Epc-homology region I and II; Bromo, bromo domain; PWWP, proline-tryptophan-tryptophan-proline-containing domain; LZ leucine zipper. Numbers correspond to total residues that each protein possesses. MOZ paralog MORF is indicated in parenthesis as it has the same domain structures/arrangement. (B) Predicted MOZ-BRPF1 complex orientation. Scaffolding subunit BRPF1 connects MOZ to ING4/5 and MEAF6. Experimentally determined histone marks/chromatin and DNA binding sites of the MOZ-BRPF1 complex are indicated. Red dots represent methylated histones and blue dots acetylated histones. Read arrow indicates acetyltransferase substrates of the complex. TF, transcription factor. (C) The MOZ-BRPF1 complex in gene activation. The complex binds to active transcription sites via acetylated H4 and/or methylated H3K4 and H3K36 and/or unmethylated CpG islands (left) or via transcription factors (TF) (right). After binding to specific chromatin regions, MOZ acetylates targeted histone lysines, which leads to opening of chromatin and induced gene expression. Individual histones in nucleosomes are indicated with different colors (upper left corner). DNA is represented by the black line Created with BioRender.com.

FIGURE 2

The MOZ-BRPF1 complex regulates various steps of development via controlling H3 acetylation levels. 1) Upon cellular stress, MOZ drives cellular senescence by interacting with PML-p53, which enhances p53 acetylation leading to expression of the p21 senescence factor. 2) MOZ is involved in embryogenesis by controlling the expression of multiple essential transcription factor families such as homeobox (HOX), T-box (TBX) and distal-less homeobox (DLX). Knockout experiments with MOZ show a decrease of H3K9ac levels at these genes, suggesting that the MOZ-BRPF1 complex regulates H3K9ac during development. H3K23ac is labeled with a question mark since its levels have not been fully addressed during MOZ KO studies. 3) MOZ and BRPF1 are crucial regulators of hematopoietic and neuronal stem cells and precursors. The MOZ-BRPF1 complex inhibits premature senescence of stem cells by downregulating the INK4a/ARF pathway. 4. Depletion of BRPF1 leads to decreased formation and motion of neurons causing neurodevelopmental defects. Loss of H3K23ac in the dorsal cortex of BRPF1 KO mice indicates that MOZ-BRPF1 or MORF-BRPF1 regulate this acetylation mark during neuronal development. Created with BioRender.com.

FIGURE 3

Mutations in MOZ and BRPF1 lead to developmental disorders and different forms of cancer. (A) MOZ is recurrently mutated in leukemia, non-hematologic malignancies, and developmental disorders with the common characteristics of intellectual disability and developmental delays. Arrows above the MOZ protein structure point to leukemia-associated translocations, the corresponding fusion partners being indicated. KAT6A syndrome refers to MOZ-specific intellectual disability disorders. For simplicity, only a few arrows below are used to illustrate mutation positions related to the KAT6A syndrome [refer to published reports for complete list of mutations (Arboleda et al., 2015; Tham et al., 2015; Kennedy et al., 2019)]. BRPF1 mutations are linked to developmental delays and cancer. Arrows above the BRPF1 protein structure indicate mutations associated with cancer (Huether et al., 2014; Kool et al., 2014; Aiello et al., 2019). Arrows below BRPF1 indicate mutations from patients with developmental disorders [modified from (Yan et al., 2020)]. Used abbreviations: CBP, CREB-binding protein; p300, E1A-associated p300 kDa protein; TIF2, transcription intermediary factor 2, ASXL2, additional sex combs-like 2; NcoA3, nuclear receptor co-activator three; leucine twenty homeobox, LEUTX. fs, reading frame shift; *, translational termination. Domain abbreviations for MOZ and BRPF1 are as in Figure 1. (B) Possible mechanisms how MOZ-BRPF1 mutations and translocations can change gene expression. 1) Mutations in the epigenetic reader domains of MOZ or BRPF1 can prevent chromatin binding on specific regions and alter gene expression (left). Mutations in the MOZ MYST domain or BRPF1 PZD domain can decrease or block the acetyltransferase activity of the complex leading to repressing chromatin structure unavailable for transcription (middle). Mutations in the C-terminal part of MOZ disrupts binding of specific (light green) transcription factors (TFs) blocking activation of genes (right). 2) Rearragements of the MOZ gene fuse the N-terminal of MOZ (indicated in A) with a fusion partner. Loss of MOZ C-terminus disrupts the complex binding to specific TFs (light green) blocking gene activation (left). The MOZ fusion protein can form a functional complex and binds to active transcription sites via BRPF1 and ING4/5 (middle). This can cause overexpression or silencing of target genes depending on the fusion partner. The MOZ complex can be recruited to fusion partner specific chromatin sites via TFs (teal) or other mechanisms leading to abnormal histone acetylation and gene expression in these sites (right) Created with BioRender.com.