Uncovering the non-histone interactome of the BRPF1 bromodomain using site-specific azide-acetyllysine photochemistry.

Bromodomain-PHD finger protein 1 (BRPF1) belongs to the BRPF family of bromodomain-containing proteins. Bromodomains are exclusive reader modules that recognize and bind acetylated histones and non-histone transcription factors to regulate gene expression. The biological functions of acetylated histone recognition by BRPF1 bromodomain are well characterized; however, the function of BRPF1 regulation via non-histone acetylation is still unexplored. Therefore, identifying the non-histone interactome of BRPF1 is pivotal in deciphering its role in diverse cellular processes, including its misregulation in diseases like cancer. Herein, we identified the non-histone interacting partners of BRPF1 utilizing a protein engineering-based approach. We site-specifically introduced the unnatural photo-cross-linkable amino acid 4-azido-L-phenylalanine into the bromodomain of BRPF1 without altering its ability to recognize acetylated histone proteins. Upon photoirradiation, the engineered BRPF1 generates a reactive nitrene species, cross-linking interacting partners with spatio-temporal precision. We demonstrated the robust cross-linking efficiency of the engineered variant with reported histone ligands of BRPF1 and further used the variant reader to cross-link its interactome. We also characterized novel interacting partners by proteomics, suggesting roles for BRPF1 in diverse cellular processes. BRPF1 interaction with interleukin enhancer-binding factor 3, one of these novel interacting partners, was further validated by isothermal titration calorimetry and co-IP. Lastly, we used publicly available ChIP-seq and RNA-seq datasets to understand the colocalization of BRPF1 and interleukin enhancer-binding factor 3 in regulating gene expression in the context of hepatocellular carcinoma. Together, these results will be crucial for full understanding of the roles of BRPF1 in transcriptional regulation and in the design of small-molecule inhibitors for cancer treatment.

Essential gene screening identifies the bromodomain-containing protein BRPF1 as a new actionable target for endocrine therapy-resistant breast cancers.

Identifying master epigenetic factors controlling proliferation and survival of cancer cells allows to discover new molecular targets exploitable to overcome resistance to current pharmacological regimens. In breast cancer (BC), resistance to endocrine therapy (ET) arises from aberrant Estrogen Receptor alpha (ERα) signaling caused by genetic and epigenetic events still mainly unknown. Targeting key upstream components of the ERα pathway provides a way to interfere with estrogen signaling in cancer cells independently from any other downstream event. By combining computational analysis of genome-wide 'drop-out' screenings with siRNA-mediated gene knock-down (kd), we identified a set of essential genes in luminal-like, ERα + BC that includes BRPF1, encoding a bromodomain-containing protein belonging to a family of epigenetic readers that act as chromatin remodelers to control gene transcription. To gather mechanistic insights into the role of BRPF1 in BC and ERα signaling, we applied chromatin and transcriptome profiling, gene ablation and targeted pharmacological inhibition coupled to cellular and functional assays. Results indicate that BRPF1 associates with ERα onto BC cell chromatin and its blockade inhibits cell cycle progression, reduces cell proliferation and mediates transcriptome changes through the modulation of chromatin accessibility. This effect is elicited by a widespread inhibition of estrogen signaling, consequent to ERα gene silencing, in antiestrogen (AE) -sensitive and -resistant BC cells and pre-clinical patient-derived models (PDOs). Characterization of the functional interplay of BRPF1 with ERα reveals a new regulator of estrogen-responsive BC cell survival and suggests that this epigenetic factor is a potential new target for treatment of these tumors.

Pygo2 activates BRPF1 via Pygo2-H3K4me2/3 interaction to maintain malignant progression in colon cancer.

Epigenetic alterations have essential roles during colon adenocarcinoma (COAD) progression. As the coactivator of Wnt/b-catenin signaling, Pygopus 2 (Pygo2) binds H3K4me2/3 and participate in chromatin remodeling in multiple cancers. However, It remains unclear whether the Pygo2-H3K4me2/3 association has significance in COAD. We aimed to elucidate the roles of Pygo2 in COAD. Functionally, Pygo2 inhibition attenuated cell proliferation, self-renewal capacities in vitro. Pygo2 overexpression enhanced in vivo tumor growth. Besides, Pygo2 overexpression could also enhance cell migration ability and in vivo distal metastasis. Mechanistically, Pygo2 correlates positively with BRPF1 expressions, one epigenetic reader of histone acetylation. The luciferase reporter assay and Chromatin Immunoprecipitation (ChIP)-qPCR assay were used to find that Pygo2 coordinated with H3K4me2/3 modifications to activate BRPF1 transcriptions via binding to the promoter. Both Pygo2 and BRPF1 expressed highly in tumors and Pygo2 relied on BRPF1 to accelerate COAD progression, including cell proliferation rate, migration abilities, stemness features and in vivo tumor growth. Targeting BPRF1 (GSK5959) is effective to suppress in vitro growth of Pygo2high cell lines, and has mild effect on Pygo2low cells. The subcutaneous tumor model further demonstrated that GSK5959 could effectively suppress the in vivo growth of Pygo2high COAD, but not the Pygo2low subtype. Collectively, our study represented Pygo2/BRPF1 as an epigenetic vulnerability for COAD treatment with predictive significance.

Anemia and thrombocytopenia due to a novel BRPF1 variant in a family from Çanakkale with intellectual disability and dysmorphic facies: Case report and review of the literature.

Intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP) (MIM#617333) is an autosomal dominant disorder characterized by delayed psychomotor development, intellectual disability (ID), and dysmorphic facial features due to pathogenic variations in the Bromodomain- and PHD Finger-Containing Protein (BRPF1) (MIM#602410) gene. Herein, we report the first Turkish patients with IDDDFP. Additionally, the patients had hematopoietic disorders such as anemia and thrombocytopenia, which have not been previously described in IDDDFP patients. Genetic testing using Whole Exome Sequencing (WES) revealed a novel heterozygous c.1433G > A; p.W478* (NM_004634.3) pathogenic variant on exon 3 of the BRPF1 gene. The patients demonstrated classical features of IDDDFP such as intellectual disability, developmental delay, ptosis, micro and retrognathia, and dysmorphic facial features, in addition to the anemia and thrombocytopenia. Apart from the variant in BRPF1, no additional genomic changes were detected by WES and chromosomal microarray analysis (CMA). Hopefully, our novel report on the hematopoietic anomalies of our patients due to BRPF1 will expand upon the clinical spectrum of IDDDFP, encourage further studies about BRPF1-hematopoietic system relations, and affect the diagnostic and therapeutic schemes of hematopoietic system disorders.

Development of 3-acetylindole derivatives that selectively target BRPF1 as new inhibitors of receptor activator of NF-κB ligand (RANKL)-Induced osteoclastogenesis.

Bromodomain and PHD finger-containing (BRPF) proteins function as epigenetic readers that specifically recognize acetylated lysine residues on histone tails. The acetyl-lysine binding pocket of BRPF has emerged as an attractive target for the development of protein interaction inhibitors owing to its potential druggability. In this study, we identified 3-acetylindoles as bone antiresorptive agents with a novel scaffold by performing structure-based virtual screening and hit optimization. Among those derivatives, compound 18 exhibited potent and selective inhibitory activities against BRPF1B (IC50 = 102 nM) as well as outstanding inhibitory activity against osteoclastogenesis (73.8% @ 1 µM) and differentiation (IC50 = 0.19 µM) without cytotoxicity. Besides, cellular mechanism assays demonstrated that compound 18 exhibited a strong bone antiresorptive effect by modulating the RANKL/RANK/NFATc1 pathway. Structural and functional studies on BRPF1 inhibitors aid in making advances to understand the epigenetic mechanisms of bone cell development and create innovative therapeutics for treating bone metastases from solid tumors and other bone erosive diseases.

BRPF1-associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development.

In 2017, Mattiolli et al. and Yan et al. described a series of patients with clinical findings essentially characterized by intellectual disabilities, ptosis, hypotonia, epilepsy, and weakness. They also found in these patients distinct heterozygous mutations in the BRPF1 gene, which plays a role in epigenetic regulation by promoting histone acetylation. The disease is known as Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP, OMIM #617333). Later, another 20 patients were also described by distinct reports, suggesting IDDDFP could be a more frequent cause of intellectual disability as it was thought before. Here, we describe a patient with normal intellectual development who had congenital ptosis, hypotonia, muscular weakness, atlanto-axial malformation, and pyramidal at the neurological examination. The patient has a rare nonsense variant on exon 3 of BRPF1 gene. We also describe a phenotypic amplification for conditions related to deficiency in histone modifications.

Pathogenic 12-kb copy-neutral inversion in syndromic intellectual disability identified by high-fidelity long-read sequencing.

We report monozygotic twin girls with syndromic intellectual disability who underwent exome sequencing but with negative pathogenic variants. To search for variants that are unrecognized by exome sequencing, high-fidelity long-read genome sequencing (HiFi LR-GS) was applied. A 12-kb copy-neutral inversion was precisely identified by HiFi LR-GS after trio-based variant filtering. This inversion directly disrupted two genes, CPNE9 and BRPF1, the latter of which attracted our attention because pathogenic BRPF1 variants have been identified in autosomal dominant intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP), which later turned out to be clinically found in the twins. Trio-based HiFi LR-GS together with haplotype phasing revealed that the 12-kb inversion occurred de novo on the maternally transmitted chromosome. This study clearly indicates that submicroscopic copy-neutral inversions are important but often uncharacterized culprits in monogenic disorders and that long-read sequencing is highly advantageous for detecting such inversions involved in genetic diseases.

Exchange of associated factors directs a switch in HBO1 acetyltransferase histone tail specificity.

Histone acetyltransferases (HATs) assemble into multisubunit complexes in order to target distinct lysine residues on nucleosomal histones. Here, we characterize native HAT complexes assembled by the BRPF family of scaffold proteins. Their plant homeodomain (PHD)-Zn knuckle-PHD domain is essential for binding chromatin and is restricted to unmethylated H3K4, a specificity that is reversed by the associated ING subunit. Native BRPF1 complexes can contain either MOZ/MORF or HBO1 as catalytic acetyltransferase subunit. Interestingly, while the previously reported HBO1 complexes containing JADE scaffold proteins target histone H4, the HBO1-BRPF1 complex acetylates only H3 in chromatin. We mapped a small region to the N terminus of scaffold proteins responsible for histone tail selection on chromatin. Thus, alternate choice of subunits associated with HBO1 can switch its specificity between H4 and H3 tails. These results uncover a crucial new role for associated proteins within HAT complexes, previously thought to be intrinsic to the catalytic subunit.

Molecular mechanisms of transcriptional regulation by the nuclear zinc-finger protein Zfat in T cells.

Zfat is a nuclear protein with AT-hook and zinc-finger domains. We previously reported that Zfat plays crucial roles in T-cell survival and development in mice. However, the molecular mechanisms whereby Zfat regulates gene expression in T cells remain unexplored. In this study, we analyzed the genome-wide occupancy of Zfat by chromatin immunoprecipitation with sequencing (ChIP-seq), which showed that Zfat bound predominantly to a region around a transcription start site (TSS), and that an 8-bp nucleotide sequence GAA(T/A)(C/G)TGC was identified as a consensus sequence for Zfat-binding sites. Furthermore, about half of the Zfat-binding sites were characterized by histone H3 acetylations at lysine 9 and lysine 27 (H3K9ac/K27ac). Notably, Zfat gene deletion decreased the H3K9ac/K27ac levels at the Zfat-binding sites, suggesting that Zfat may be related to the regulation of H3K9ac/K27ac. Integrated analysis of ChIP-seq and transcriptional profiling in thymocytes identified Zfat-target genes with transcription to be regulated directly by Zfat. We then focused on the chromatin regulator Brpf1, a Zfat-target gene, revealing that Zfat bound directly to a 9-bp nucleotide sequence, CGAANGTGC, which is conserved among mammalian Brpf1 promoters. Furthermore, retrovirus-mediated re-expression of Zfat in Zfat-deficient peripheral T cells restored Brpf1 expression to normal levels, and shRNA-mediated Brpf1 knockdown in peripheral T cells increased the proportion of apoptotic cells, suggesting that Zfat-regulated Brpf1 expression was important for T-cell survival. Our findings demonstrated that Zfat regulates the transcription of target genes by binding directly to the TSS proximal region, and that Zfat-target genes play important roles in T-cell homeostasis.

Deficiency of the chromatin regulator BRPF1 causes abnormal brain development.

Epigenetic mechanisms are important in different neurological disorders, and one such mechanism is histone acetylation. The multivalent chromatin regulator BRPF1 (bromodomain- and plant homeodomain-linked (PHD) zinc finger-containing protein 1) recognizes different epigenetic marks and activates three histone acetyltransferases, so it is both a reader and a co-writer of the epigenetic language. The three histone acetyltransferases are MOZ, MORF, and HBO1, which are also known as lysine acetyltransferase 6A (KAT6A), KAT6B, and KAT7, respectively. The MORF gene is mutated in four neurodevelopmental disorders sharing the characteristic of intellectual disability and frequently displaying callosal agenesis. Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis. With respect to the control, the mutant forebrain contained fewer Tbr2-positive intermediate neuronal progenitors and displayed aberrant neurogenesis. Molecularly, Brpf1 loss led to decreased transcription of multiple genes, such as Robo3 and Otx1, important for neocortical development. Surprisingly, elevated expression of different Hox genes and various other transcription factors, such as Lhx4, Foxa1, Tbx5, and Twist1, was also observed. These results thus identify an important role of Brpf1 in regulating forebrain development and suggest that it acts as both an activator and a silencer of gene expression in vivo.

MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease.

Lysine residues are subject to many forms of covalent modification and one such modification is acetylation of the ε-amino group. Initially identified on histone proteins in the 1960s, lysine acetylation is now considered as an important form of post-translational modification that rivals phosphorylation. However, only about a dozen of human lysine acetyltransferases have been identified. Among them are MOZ (monocytic leukemia zinc finger protein; a.k.a. MYST3 and KAT6A) and its paralog MORF (a.k.a. MYST4 and KAT6B). Although there is a distantly related protein in Drosophila and sea urchin, these two enzymes are vertebrate-specific. They form tetrameric complexes with BRPF1 (bromodomain- and PHD finger-containing protein 1) and two small non-catalytic subunits. These two acetyltransferases and BRPF1 play key roles in various developmental processes; for example, they are important for development of hematopoietic and neural stem cells. The human KAT6A and KAT6B genes are recurrently mutated in leukemia, non-hematologic malignancies, and multiple developmental disorders displaying intellectual disability and various other abnormalities. In addition, the BRPF1 gene is mutated in childhood leukemia and adult medulloblastoma. Therefore, these two acetyltransferases and their partner BRPF1 are important in animal development and human disease.

Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases.

INTRODUCTION: BRPF1 gene on 3p26-p25 encodes a protein involved in epigenetic regulation, through interaction with histone H3 lysine acetyltransferases KAT6A and KAT6B of the MYST family. Heterozygous pathogenic variants in BRPF1 gene are associated with Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP), characterized by global developmental delay, intellectual disability, language delay, and dysmorphic facial features. The reported ocular involvement includes strabismus, amblyopia, and refraction errors. This report describes a novel ocular finding in patients affected by variants in the BRPF1 gene. METHODS: We performed exome sequencing and deep ocular phenotyping in two unrelated patients (P1, P2) with mild intellectual disability, ptosis, and typical facies. RESULTS: Interestingly, P1 had a Chiari Malformation type I and a subclinical optic neuropathy, which could not be explained by variations in other genes. Having detected a peculiar ocular phenotype in P1, we suggested optical coherence tomography (OCT) for P2; such an exam also detected bilateral subclinical optic neuropathy in this case. DISCUSSION: To date, only a few patients with BRPF1 variants have been described, and none were reported to have optic neuropathy. Since subclinical optic nerve alterations can go easily undetected, our experience highlights the importance of a more detailed ophthalmologic evaluation in patients with BRPF1 variant.

Beyond 'speech delay': Expanding the phenotype of BRPF1-related disorder.

Pathogenic variants in BRPF1 cause intellectual disability, ptosis and facial dysmorphism. Speech and language deficits have been identified as a manifestation of BRPF1-related disorder but have not been systematically characterized. We provide a comprehensive delineation of speech and language abilities in BRPF1-related disorder and expand the phenotype. Speech and language, and health and medical history were assessed in 15 participants (male = 10, median age = 7 years 4 months) with 14 BRPF1 variants. Language disorders were common (11/12), and most had mild to moderate deficits across receptive, expressive, written, and social-pragmatic domains. Speech disorders were frequent (7/9), including phonological delay (6/9) and disorder (3/9), and childhood apraxia of speech (3/9). All those tested for cognitive abilities had a FSIQ ≥70 (4/4). Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15). We have implicated BRPF1-related disorder as causative for speech and language disorder, including childhood apraxia of speech. Adaptive behavior and cognition were strengths when compared to other monogenic neurodevelopmental chromatin-related disorders. The universal involvement of speech and language impairment is noteable, relative to the high degree of phenotypic variability in BRPF1-related disorder.

Accelerating BRPF1b hit identification with BioPhysical and Active Learning Screening (BioPALS).

We report the development of BioPhysical and Active Learning Screening (BioPALS); a rapid and versatile hit identification protocol combining AI-powered virtual screening with a GCI-driven biophysical confirmation workflow. Its application to the BRPF1b bromodomain afforded a range of novel micromolar binders with favorable ADMET properties. In addition to the excellent in silico/in vitro confirmation rate demonstrated with BRPF1b, binding kinetics were determined, and binding topologies predicted for all hits. BioPALS is a lean, data-rich, and standardized approach to hit identification applicable to a wide range of biological targets.

Integrated virtual screening and MD simulation approaches toward discovering potential inhibitors for targeting BRPF1 bromodomain in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most aggressive and life-threatening cancers. Although multiple treatment options are available, the prognosis of HCC patients is poor due to metastasis and drug resistance. Hence, discovering novel targets is essential for better therapeutic development for HCC. In this study, we used the cancer genome atlas (TCGA) dataset to analyze the expression of bromodomain-containing proteins in HCC, as bromodomains are emerging attractive therapeutic targets. Our analysis identified BRPF1 as the most highly upregulated gene in HCC among the 43 bromodomain-containing genes. Upregulation of BRPF1 was significantly associated with poorer patient survival. Therefore, targeting BRPF1 may be an approach for HCC treatment. Previously, several potential inhibitors of BRPF1 bromodomain have been discovered. However, due to the limited clinical success of the current inhibitors, we aim to search for new inhibitors with high affinity and specificity for the BRPF1 bromodomain. In this study, we utilized high-throughput virtual screening methods to screen synthetic and natural compound databases against the BRPF1 bromodomain. In addition, we used machine learning-based QSAR modeling to predict the IC50 values of the selected BRPF1 bromodomain inhibitors. Extensive MD simulations were used to calculate the binding free energies of BRPF1 bromodomain and inhibitor complexes. Using this approach, we identified four lead scaffolds with a similar or better binding affinity towards the BRPF1 bromodomain than the previously reported inhibitors. Overall, this study discovered some promising compounds that have the potential to act as potent BRPF1 bromodomain inhibitors.

Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.

Bromodomain and plant homeodomain (PHD) finger containing protein 1 (Brpf1) is an activator and scaffold protein of a multiunit complex that includes other components involving lysine acetyltransferase (KAT) 6A/6B/7. Brpf1, KAT6A, and KAT6B mutations were identified as the causal genes of neurodevelopmental disorders leading to intellectual disability. Our previous work revealed strong and specific expression of Brpf1 in both the postnatal and adult forebrain, especially the hippocampus, which has essential roles in learning and memory. Here, we hypothesized that Brpf1 plays critical roles in the function of forebrain excitatory neurons, and that its deficiency leads to learning and memory deficits. To test this, we knocked out Brpf1 in forebrain excitatory neurons using CaMKIIa-Cre. We found that Brpf1 deficiency reduced the frequency of miniature excitatory postsynaptic currents and downregulated the expression of genes Pcdhgb1, Slc16a7, Robo3, and Rho, which are related to neural development, synapse function, and memory, thereby damaging spatial and fear memory in mice. These findings help explain the mechanisms of intellectual impairment in patients with BRPF1 mutation.

Discovery, optimization and evaluation of 1-(indolin-1-yl)ethan-1-ones as novel selective TRIM24/BRPF1 bromodomain inhibitors.

TRIM24 (tripartite motif-containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are epigenetics "readers" and potential therapeutic targets for cancer and other diseases. Here we describe the structure-guided design of 1-(indolin-1-yl)ethan-1-ones as novel TRIM24/BRPF1 bromodomain inhibitors. The representative compound 20l (Y08624) is a new TRIM24/BRPF1 dual inhibitor, with IC50 values of 0.98 and 1.16 µM, respectively. Cellular activity of 20l was validated by viability assay in prostate cancer (PC) cell lines. In PC xenograft models, 20l suppressed tumor growth (50 mg/kg/day, TGI = 53%) without exhibiting noticeable toxicity. Compound 20l represents a versatile starting point for the development of more potent TRIM24/BRPF1 inhibitors.

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

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.

Computational studies with flavonoids and terpenoids as BRPF1 inhibitors: in silico biological activity prediction, molecular docking, molecular dynamics simulations, MM/PBSA calculations.

The BRPF1 protein is encoded by the BRPF1 gene. In addition, the BRPF1 gene is known to be upregulated in leukaemia. Recent studies have shown that it is also overexpressed in hepatocellular carcinoma (HCC) as well. Therefore, BRPF1 is a significant target for anti-cancer drug development studies, especially on HCC. 40 terpenoids and flavonoids were chosen because of their anticancer properties given in the literature. In this study, the biological activity of molecules was also investigated with in silico structure-activity relationship analysis. In addition, interactions between a series of terpenoids and flavonoids and the BRPF1 protein were investigated by molecular docking and molecular dynamics simulations. The energy change caused by the interactions of BRPF1 with different compounds was also evaluated by MM/PBSA calculations. It has been revealed that compound 5 (-9.2 kcal/mol), a kind of secoclerodane type diterpenoid, has a higher affinity both compared to other flavonoids and terpenoids, and 9F9 (-7.9 kcal/mol), a selective BRPF1 inhibitor. The study presented in this article demonstrates that compound 5, as a natural product, could form a chemical scaffold for the development of selective BRPF1 bromodomain inhibitors.

BRPF1-KAT6A/KAT6B Complex: Molecular Structure, Biological Function and Human Disease.

The bromodomain and PHD finger-containing protein1 (BRPF1) is a member of family IV of the bromodomain-containing proteins that participate in the post-translational modification of histones. It functions in the form of a tetrameric complex with a monocytic leukemia zinc finger protein (MOZ or KAT6A), MOZ-related factor (MORF or KAT6B) or HAT bound to ORC1 (HBO1 or KAT7) and two small non-catalytic proteins, the inhibitor of growth 5 (ING5) or the paralog ING4 and MYST/Esa1-associated factor 6 (MEAF6). Mounting studies have demonstrated that all the four core subunits play crucial roles in different biological processes across diverse species, such as embryonic development, forebrain development, skeletal patterning and hematopoiesis. BRPF1, KAT6A and KAT6B mutations were identified as the cause of neurodevelopmental disorders, leukemia, medulloblastoma and other types of cancer, with germline mutations associated with neurodevelopmental disorders displaying intellectual disability, and somatic variants associated with leukemia, medulloblastoma and other cancers. In this paper, we depict the molecular structures and biological functions of the BRPF1-KAT6A/KAT6B complex, summarize the variants of the complex related to neurodevelopmental disorders and cancers and discuss future research directions and therapeutic potentials.