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Discovery of Histone Deacetylase Inhibitor Using Molecular Modeling and Free Energy Calculations.

The histone acetylation-deacetylation at lysine regulates the functions of many cellular proteins. An increased expression of HDAC6 can cause an increased amount of deacetylated histones, which leads to an inhibition of gene expression and has been associated with cancer cell proliferation. The present study screened the ZINC database to find novel HDAC6 inhibitors using virtual high-throughput screening techniques. The docking score, free energy, and binding pattern of the complexes were used to select a best ligand for further study. Molecular dynamic simulations, binding interactions, and t…

Epigenetic modulation: Research progress on histone acetylation levels in major depressive disorders.

Depression is a serious mental illness and a prevalent condition with multiple aetiologies. The impact of the current therapeutic strategies is limited and the pathogenesis of the illness is not well understood. According to previous studies, depression onset is influenced by a variety of environmental and genetic factors, including chronic stress, aberrant changes in gene expression, and hereditary predisposition. Transcriptional regulation in eukaryotes is closely related to chromosome packing and is controlled by histone post-translational modifications. The development of new antidepressan

The Art of Packaging the Sperm Genome: Molecular and Structural Basis of the Histone-To-Protamine Exchange.

Male fertility throughout life hinges on the successful production of motile sperm, a developmental process that involves three coordinated transitions: mitosis, meiosis, and spermiogenesis. Germ cells undergo both mitosis and meiosis to generate haploid round spermatids, in which histones bound to the male genome are replaced with small nuclear proteins known as protamines. During this transformation, the chromatin undergoes extensive remodeling to become highly compacted in the sperm head. Despite its central role in spermiogenesis and fertility, we lack a comprehensive understanding of the …

Histone deacetylase 1 in patients with alopecia areata and acne vulgaris: An epigenetic alteration.

BACKGROUND: Histone deacetylase 1 (HDAC1) belongs to class I histone deacetylases, which are zinc-dependent enzymes that remove the acetyl group from histones and other proteins providing epigenetic regulation of gene expression. It plays an important role in the hair follicle and epidermal homeostasis in addition to its immunomodulatory roles. Alopecia areata (AA) and acne vulgaris are common skin diseases in which epigenetic factors have been proposed. However, studies of epigenetic modifications in both diseases are quite limited. OBJECTIVE: This study aimed at elucidation of HDAC1 deregul…

Jumonji Histone Demethylase Inhibitor JIB-04 as a Broad-Spectrum Antifungal Agent.

Invasive fungal infections are emerging as a global public health problem. The lack of effective antifungal drugs is the bottleneck of clinical antifungal treatment. To identify novel antifungal agents with new mechanisms of action, JIB-04, a Jumonji histone demethylase inhibitor, was identified to possess broad-spectrum antifungal activity by a cell-based screen. Particularly, JIB-04 effectively inhibited Jumonji demethylase activity and ergosterol biosynthesis of Cryptococcus neoformans cells, leading to in vitro and in vivo anti-Cryptococcus activity. It also significantly inhibited the vir

Putative SET-domain methyltransferases in Cryptosporidium parvum and histone methylation during infection.

Cryptosporidium parvum is a leading cause of diarrhoeal illness worldwide being a significant threat to young children and immunocompromised patients, but the pathogenesis caused by this parasite remains poorly understood. C. parvum was recently linked with oncogenesis. Notably, the mechanisms of gene expression regulation are unexplored in Cryptosporidium and little is known about how the parasite impact host genome regulation. Here, we investigated potential histone lysine methylation, a dynamic epigenetic modification, during the life cycle of the parasite. We identified SET-domain containi

Phosphorylation of the Canonical Histone H2A Marks Foci of Damaged DNA in Malaria Parasites.

Plasmodium falciparum parasites proliferate within circulating red blood cells and are responsible for the deadliest form of human malaria. These parasites are exposed to numerous intrinsic and external sources that could cause DNA damage; therefore, they have evolved efficient mechanisms to protect their genome integrity and allow them to proliferate under such conditions. In higher eukaryotes, double-strand breaks rapidly lead to phosphorylation of the core histone variant H2A.X, which marks the site of damaged DNA. We show that in P. falciparum that lacks the H2A.X variant, the canonical P.

Structural insights into histone chaperone Asf1 and its characterization from Plasmodium falciparum.

Asf1 is a highly conserved histone chaperone that regulates tightly coupled nucleosome assembly/disassembly process. We observed that Plasmodium falciparum Asf1 (PfAsf1) is ubiquitously expressed in different stages of the life cycle of the parasite. To gain further insight into its biological activity, we solved the structure of N-terminal histone chaperone domain of PfAsf1 (1-159 amino acids) by X-ray crystallography to a resolution of 2.4 Å. The structure is composed of two beta-sheet to form a beta-sandwich, which resembles an immunoglobulin-like fold. The surface-charge distribution of Pf

The Role of the Histone Methyltransferase PfSET10 in Antigenic Variation by Malaria Parasites: a Cautionary Tale.

The virulence of the malaria parasite Plasmodium falciparum is due in large part to its ability to avoid immune destruction through antigenic variation. This results from changes in expression within the multicopy var gene family that encodes the surface antigen P. falciparum erythrocyte protein one (PfEMP1). Understanding the mechanisms underlying this process has been a high-profile research focus for many years. The histone methyltransferase PfSET10 was previously identified as a key enzyme required both for parasite viability and for regulating var gene expression, thus making it a promine

Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms.

Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune

Paediatric Gliomas: BRAF and Histone H3 as Biomarkers, Therapy and Perspective of Liquid Biopsies.

Paediatric gliomas categorised as low- or high-grade vary markedly from their adult counterparts, and denoted as the second most prevalent childhood cancers after leukaemia. As compared to adult gliomas, the studies of diagnostic and prognostic biomarkers, as well as the development of therapy in paediatric gliomas, are still in their infancy. A body of evidence demonstrates that B-Raf Proto-Oncogene or V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) and histone H3 mutations are valuable biomarkers for paediatric low-grade gliomas (pLGGs) and high-grade gliomas (pHGGs). Various diagnostic

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… Histone H3 mutations were first discovered in pHGGs in 2012, and the histone H3K27M mutation constitutes most of the somatic mutations in diffuse midline glioma [ 16 ]. Histone mutations are highly prevalent in pHGGs in comparison to other forms of malignancies [ 17 , 18 ]. … These essential proteins are divided into core histones (H2A, H2B, H3 and H4) and linker histones (H1 or H5) [ 55 ]. The core histones are found at the centre of nucleosomes, while linker histones interact with the nucleosomes and the linker DNA located between two nucleosomes. …

Caenorhabditis elegans establishes germline versus soma by balancing inherited histone methylation.

Formation of a zygote is coupled with extensive epigenetic reprogramming to enable appropriate inheritance of histone methylation and prevent developmental delays. In Caenorhabditis elegans, this reprogramming is mediated by the H3K4me2 demethylase SPR-5 and the H3K9 methyltransferase, MET-2. In contrast, the H3K36 methyltransferase MES-4 maintains H3K36me2/3 at germline genes between generations to facilitate re-establishment of the germline. To determine whether the MES-4 germline inheritance pathway antagonizes spr-5; met-2 reprogramming, we examined the interaction between these two pathwa

Inhibition of histone deacetylase 5 ameliorates abnormalities in 16p11.2 duplication mouse model.

Microduplication of the human 16p11.2 gene locus is associated with a range of neurodevelopmental outcomes, including autism spectrum disord … enetic enzyme repressing gene expression via removal of transcription-permissive acetyl groups from histones. Here we report that HDAC5 expression is elevated and histone acetylation is reduced at the Npas4 promoter in PFC of 16p11.2dp/+ mice. Treatment with the HDAC5 inhibitor LMK235 normalizes histone acetylation, restores GABAergic signaling in PFC, and …

KDM6A, a histone demethylase, regulates stress hematopoiesis and early B-cell differentiation.

Histone methylases and demethylases regulate gene expression programs in hematopoiesis. The molecular function of the demethylase KDM6A in normal hematopoiesis and, in particular, for the hematopoietic stem and progenitor cell (HSPC) compartment remains only partially understood. Female but not male Kdm6a-/- HSPCs were functionally impaired in adoptive transfer experiments as well as upon proliferative stress induced by 5-fluorouracil. Loss of Kdm6a affected primarily early B cells and erythroid and myeloid progenitor cells with respect to both number and function. Global gene expression analy

Histone deacetylase 3 aberration inhibits Klotho transcription and promotes renal fibrosis.

Development of renal fibrosis is a hallmark of renal aging and chronic kidney disease of all etiologies and characterized by extensive renal cell injuries and subsequent myofibroblast transdifferentiations (MTDs), which are significantly influenced by aberrant histone deacetylase (HDAC) activities. However, the key HDAC isoforms and effectors that are causally involved in the processes remain poorly understood. Here, we report that aberrant HDAC3 induction and its inhibition of Klotho, a renal epithelium-enriched aging suppressor, contribute significantly to renal fibrogenesis. HDAC3 was prefe

Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression.

Jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, specifically catalyzes the demethylation of H3K27 (H3K27me3) and regulates gene expression. Sestrin2 (SESN2), a stress-inducible protein, protected against doxorubicin (DOX)-induced cardiomyopathy by regulating mitophagy and mitochondrial function. Here, the expression of JMJD3 was increased and that of SESN2 was decreased in both the heart samples from patients with dilated cardiomyopathy and chronic DOX-stimulation induced cardiomyopathy. Inhibition or knockdown of JMJD3 attenuated DOX-induced cardiomyocytes apoptosi

Chidamide combined with paclitaxel effectively reverses the expression of histone deacetylase in lung cancer.

The role of histone deacetylases (HDACs) in lung cancer has been extensively studied. Inhibition of HDAC activities have been used as a new cancer treatment strategy. To date, many HDAC inhibitors have been shown to induce apoptosis and inhibit tumorigenesis. Chidamide (CS055) is a new member of HDAC inhibitors. In China, Chidamide has been approved for the treatment of relapsed or refractory peripheral T-cell lymphoma. However, the efficacy of Chidamide in non-small cell lung cancer remains unclear. In this study, we used lung cancer primary cells and investigated the effects of Chidamide com

Inhibition of PfMYST Histone Acetyltransferase Activity Blocks Plasmodium falciparum Growth and Survival.

One of the major barriers in the prevention and control of malaria programs worldwide is the growing emergence of multidrug resistance in Plasmodium parasites, and this necessitates continued efforts to discover and develop effective drug molecules targeting novel proteins essential for parasite survival. In recent years, epigenetic regulators have evolved as an attractive drug target option owing to their crucial role in survival and development of Plasmodium at different stages of its life cycle. PfMYST, a histone acetyltransferase protein, is known to regulate key cellular processes, such a

Effect of histone demethylase KDM5A on the odontogenic differentiation of human dental pulp cells.

Human dental pulp cells (hDPCs) possess the capacity to differentiate into odontoblast-like cells in response to exogenous stimuli. Histone methylation is one of the most robust epigenetic marks and is essential for the regulation of multiple cellular processes. Previous studies have shown that histone methyltransferases (HMTs) and histone demethylases (HDMs) are crucial for the osteogenic differentiation of human bone marrow, adipose tissue, and tooth tissue. However, little is known about the role of histone methylation in hDPC differentiation. Here, the expression levels of HMTs and HDMs we

A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer.

The emergence of tumour recurrence and resistance limits the survival rate for most tumour-bearing patients. Only, combination therapies targeting pathways involved in the induction and in the maintenance of cancer growth and progression might potentially result in an enhanced therapeutic efficacy. Herein, we provided a prospective combination treatment that includes suberoylanilide hydroxamic acid (SAHA), a well-known inhibitor of histone deacetylases (HDACs), and SLC-0111, a novel inhibitor of carbonic anhydrase (CA) IX. We proved that HDAC inhibition with SAHA in combination with SLC-0111 a