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Isolation, characterisation and organisation of histone H1 genes in African trypanosomes.

A tandemly arranged gene family coding for histone H1 in African trypanosomes is described. Many variants, differing by some substitutions and/or deletions in their monotone and repetitive amino acid sequences, are found. The different variants can be sorted into three subtypes using their N-terminal region. PCR amplification experiments with primers specific to these three H1 subtypes suggest that the genes may be separated into two transcriptional units. Heterogeneity among species, subspecies and even strains was found. The transcripts are polyadenylated and the trans-splicing site is locat

The monocytic leukemia zinc finger protein MOZ is a histone acetyltransferase.

The monocytic leukemia zinc finger protein (MOZ) gene is rearranged in t(8;16)(p11;p13), t(8;22)(p11;q13) and inv(8)(p11q13) associated with acute myeloid leukemia. The other fusion partners involved are CBP, p300 and TIF2, transcriptional coactivators with known or potential histone acetyltransferase (HAT) activity. MOZ itself is a 2004-residue protein containing a putative acetyl CoA-binding motif, so it was hypothesized that MOZ is a HAT. Here we present direct evidence that MOZ has intrinsic HAT activity. Moreover, MOZ possesses a transcriptional repression domain at its N-terminal part an

The ADA complex is a distinct histone acetyltransferase complex in Saccharomyces cerevisiae.

We have identified two Gcn5-dependent histone acetyltransferase (HAT) complexes from Saccharomyces cerevisiae, the 0.8-MDa ADA complex and the 1.8-MDa SAGA complex. The SAGA (Spt-Ada-Gcn5-acetyltransferase) complex contains several subunits which also function as part of other protein complexes, including a subset of TATA box binding protein-associated factors (TAFIIs) and Tra1. These observations raise the question of whether the 0.8-MDa ADA complex is a subcomplex of SAGA or whether it is a distinct HAT complex that also shares subunits with SAGA. To address this issue, we sought to determin

Histone H3 thiol reactivity and acetyltransferases in chicken erythrocyte nuclei.

Chicken erythrocyte nuclei previously incubated separately with two novel mercury compounds (N-chloromercuribenzoyl)-biocytin and bis(p-(chl … also contained the highest proportion of bound mercury. This fraction contains hyperacetylated core histones, is depleted in linker histones, and enriched in nonhistone proteins. Histone H3 in the 0.15 M NaCl-soluble mononucleosomes, which are unacetylated and lack linker histones, was 45% less labeled than histone H3 in the 0.15 M NaCl-soluble polynucleos …

Effect of vitamin A deficiency on the testis-specific histone TH2B of the rat.

The effect of vitamin A deficiency on rat testis was studied biochemically and histologically. The earliest change in nuclear basic proteins was a decrease and disappearance of the testis-specific protein (TP); the disappearance approximately coincided with cessation of growth. At later stages of deficiency, the testis-specific histone TH2B was markedly reduced and in some cases disappeared, as did the TH1 histone band. Histological studies indicated that the loss of TH2B and TH1 requires a substantial degree of testicular degeneration, because they could still be detected to some extent in te

Histone H2B variants from the erythrocytes of an amphibian, a reptile and a bird.

Histones H2B have been isolated from the terminally differentiated diploid erythrocytes of three different classes, amphibia (Xenopus laevis), reptilia (Crocodilus niloticus) and aves (Gallus domesticus). Partial amino acid sequences revealed three regions of sequence variation, each variant involving a single amino acid substitution.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells.

Neutrophil extracellular traps (NETs) can capture and kill viruses, such as influenza viruses, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV), thus contributing to host defense. Contrary to our expectation, we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2, as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model. The histone H3 or H4 selectively binds to subunit 2 of the spike (S) protein, as shown by a biochemical binding assay, surface plasmon resonance and binding energy calculation as well as t…

Helical Peptidomimetic Inhibitors Targeting the Histone Chaperone ASF1 for Cancer Therapy.

Targeting protein-protein interactions (PPIs) with shallow, extended interfaces remains challenging, as exemplified by the histone chaperone ASF1. Here, we report de novo designed d-sulfonyl-γ-AApeptide foldamers that mimic the hot-spot residues of the histone H3 C-terminal α-helix that are essential for ASF1 recognition. The lead compound ASF-015 shows high-affinity binding to ASF1A and potent antiproliferative activity across cancer cell lines. These foldamers, completely resistant to proteolytic degradation, penetrate cells without a cell-penetrating peptide, engage intracellular ASF1, disr

The Crosstalk Between Metabolic Reprogramming and Histone Methylation in Tumor Immunity and Immunotherapy.

Histone methylation regulates chromatin structure and gene expression, whereas tumor metabolism provides bioenergetic and biosynthetic inputs. These processes are bidirectionally linked: S-adenosylmethionine supplies methyl groups for histone methyltransferases, α-ketoglutarate(α-KG) supports JmjC-domain demethylases, and D-2-hydroxyglutarate (D-2HG) can inhibit α-KG-dependent dioxygenases. Conversely, histone methylation can regulate metabolic gene expression, as illustrated by KMT2D-dependent enhancer remodeling and glycolytic gene expression in melanoma models. Lactate regulates chromatin t

The role of histone modification in epigenetic regulation of gene expression and cell specification.

During development and differentiation, each cell of multicellular organisms acquires properties fundamental for its specific functions; thi … mulation, and neurotransmission. The main proteins involved in chromatin structure organization are histones, which can be modified in many ways, and that also exist as isoforms (histone variants), with different structural and functional effects on chromatin. Thanks to sequential epigenetic modifications, cells acquire a memory of their past, stored in th …

The histone variant H2A.Z regulates sex differences in Alzheimer's disease pathophysiology.

Alzheimer's disease (AD) disproportionately affects women, yet mechanisms underlying this sex difference remain unclear. Histone variants are overrepresented components of aging neuronal chromatin, but their contribution to AD is unknown. Here, we identify the histone variant H2A.Z as a sex-specific regulator of AD in the postmortem human hippocampus and in 5xFAD mice. H2A.Z occupancy decreased in female but increased in male AD patients. In females, reduced H2A.Z occupancy at the transcription start site (TSS) occurred despite increased total H2A.Z, indicating that H2A.Z is redistributed to s

Histone Demethylase KDM5A Is Activated and Pathogenic in a Mouse Model of LMNA-Cardiomyopathy.

Heart failure is associated with widespread epigenetic remodeling in cardiomyocytes, but the chromatin regulators driving this process remain poorly defined. We identify the histone H3K4 demethylase KDM5A as a key epigenetic mediator of heart failure in a cardiomyocyte-specific lamin A-deficient mouse model. Disease-associated activation of KDM5A leads to redistribution of promoter histone H3 lysine 4 trimethylation and repression of genes regulating sarcomere structure and mitochondrial oxidative metabolism. Genetic deletion of Kdm5a restores histone H3 lysine 4 trimethylation enrichment, rea

Histone lysine demethylase inhibition is a disease-modifying therapy for hypertrophic cardiomyopathy.

RATIONALE: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder characterized by cardiac hypertrophy, fibrosis, arrhythmias, and sudden cardiac death (SCD). Although current therapies primarily target sarcomere dysfunction, the contribution of epigenetic dysregulation to HCM pathogenesis and its therapeutic potential remain poorly understood. OBJECTIVE: To determine whether pharmacological inhibition of histone lysine demethylases (KDMs) with JIB-04 can prevent or reverse HCM progression and to identify the underlying epigenetic mechanisms. METHODS AND RESULTS: We evaluat

Pharmacological inhibition of histone Lactylation enhances immunotherapy efficacy in gastrointestinal cancers.

Although immunotherapy has reshaped the treatment landscape for gastrointestinal (GI) malignancies, durable clinical benefit is achieved in only a subset of patients, largely due to the emergence of immune resistance. Accumulating evidence highlights histone lactylation, an epigenetic modification driven by excessive lactate accumulation, as a pivotal mediator linking tumor metabolism to immune suppression. By reprogramming transcriptional networks within the tumor microenvironment, histone lactylation skews macrophages toward an immunosuppressive phenotype and compromises T-cell effector func

Single-cell analysis reveals neuroprotective histone deacetylase inhibitor pathways.

INTRODUCTION: Alzheimer's disease (AD) involves β-amyloid (Aβ) accumulation, tau pathology, and neuroinflammation, driving cognitive decline. Despite extensive research, disease-modifying therapies remain elusive. We integrated single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and in vitro validation to identify repurposable drugs for AD1. METHODS: Computational drug repurposing was performed using cell-type-specific analysis of scRNA-seq datasets from AD cortical regions. Trichostatin-A (TSA) effects were validated in human induced pluripotent stem cells (iPSC) -derived cortic

Histone Deacetylase Meets Protein Degradation: Accelerating Anticancer Drug Discovery.

Histone deacetylases (HDACs) are key epigenetic regulators involved in a variety of cancers, rendering them attractive therapeutic targets. Although several HDAC inhibitors have achieved clinical success, challenges such as poor isoform selectivity, acquired resistance, and off-target toxicity limit their broader application. Proteolysis-targeting chimeras (PROTACs) represent an innovative therapeutic strategy that enables ubiquitin-proteasome-mediated degradation of HDACs. This approach enhances specificity, overcomes resistance mechanisms, including those resulting from point mutations or pe

Histone methylation machinery in gliomas: From enzymatic mechanisms to inhibitor development.

Glioma is the most common primary malignant tumor of the central nervous system (CNS). Advances in molecular pathology have established a robust causal link between histone modifications and glioma genesis. In addition to prior findings, recent empirical evidence has unequivocally substantiated the intricate and close relationship between histone modifications and temozolomide (TMZ) resistance, thereby advancing our understanding in this field. This article systematically reviews the roles of histone methylation modifications in glioma pathogenesis and their implications for the mechanisms of

Epigenetic Dysregulation in Neurodegeneration: The Role of Histone Deacetylases and Emerging Inhibitor Strategies.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanis

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… The histone deacetylase (HDAC) enzyme family has received significant attention among these. Since our focus is primarily on histone modifications, it is important to outline the diverse post-translational changes histones can undergo. … By eliminating acetyl and other acyl groups from lysine residues on histone and non-histone proteins, histone deacetylases (HDACs) are important epigenetic enzymes that affect transcription, cell differentiation, DNA replication, and the cell cycle [ 26 ]. …

Selective histone deacetylase inhibition as a therapeutically relevant strategy in H3K27M-glioma.

BACKGROUND: Diffuse midline glioma (DMG) is a lethal pediatric brain tumor, driven by profound epigenetic dysregulation, raising the possibility that targeting epigenetic regulators such as histone deacetylases (HDACs) could provide a therapeutic benefit. However, despite preclinical activity, currently available HDAC inhibitors have shown limited clinical translation due to poor central nervous system (CNS) penetration and a lack of HDAC isoform selectivity. METHODS: We combined CRISPR/Cas9 screening and pharmacologic HDAC inhibition to identify isoform-specific dependencies in DMG cell line