Kdm6B

BACKGROUND: NAFLD caused by abnormalities in hepatic lipid metabolism is associated with an increased risk of developing HCC. The molecular mechanisms underlying the progression of NAFLD-related HCC are not fully understood. We investigated the molecular mechanism and role of KDM6B downregulation in NAFLD-related HCC after the KDM6B gene was identified using microarray analysis as commonly downregulated in mouse NAFLD-related HCC and human nonhepatitis B and nonhepatitis C viral-HCC. METHODS: The 5-hydroxymethylcytosine levels of KDM6B in HCC cells were determined using glycosylated hydroxymethyl-sensitive PCR...

AIMS: Nerve injury-induced mechanical hypersensitivity is one of major clinical symptoms in neuropathic pain patients. Understanding molecular mechanisms underlying this symptom is crucial for developing effective therapies. The present study was to investigate whether sensory neuron-specific long noncoding RNA (SS-lncRNA) predominantly expressed in small non-peptidergic dorsal root ganglion (DRG) neurons repaired nerve injury-induced mechanical hypersensitivity. MATERIALS AND METHODS: SS-lncRNA downregulation in the mas-related G protein-coupled receptor member D (Mrgprd)-expressed DRG neurons was rescued and mimicked by crossbreeding MrgprdCreERT2/+ lines with Rosa26SS-lncRNA knock-in mice and SS-lncRNAfl/fl mice, respectively, followed by tamoxifen injection...

ACOX1: acyl-CoA oxidase 1; ADH5: alcohol dehydrogenase 5 (class III), chi polypeptide; ADIPOQ: adiponectin, C1Q and collagen domain containing; ATG: autophagy related; BECN1: beclin 1; CRTC2: CREB regulated transcription coactivator 2; ER: endoplasmic reticulum; F2RL1: F2R like trypsin receptor 1; FA: fatty acid; FOXO1: forkhead box O1; GLP1R: glucagon like peptide 1 receptor; GRK2: G protein-coupled receptor kinase 2; GTPase: guanosine triphosphatase; HFD: high-fat diet; HSCs: hepatic stellate cells; HTRA2: HtrA serine peptidase 2; IRGM: immunity related GTPase M; KD: knockdown; KDM6B: lysine demethylase 6B; KO: knockout; LAMP2: lysosomal associated membrane protein 2; LAP: LC3-associated phagocytosis; LDs: lipid droplets; Li KO: liver-specific knockout; LSECs: liver sinusoidal endothelial cells; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K5: mitogen-activated protein kinase kinase kinase 5; MED1: mediator complex subunit 1; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin complex 1; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; NFE2L2: NFE2 like bZIP transcription factor 2; NOS3: nitric oxide synthase 3; NR1H3: nuclear receptor subfamily 1 group H member 3; OA: oleic acid; OE: overexpression; OSBPL8: oxysterol binding protein like 8; PA: palmitic acid; RUBCNL: rubicon like autophagy enhancer; PLIN2: perilipin 2; PLIN3: perilipin 3; PPARA: peroxisome proliferator activated receptor alpha; PRKAA2/AMPK: protein kinase AMP-activated catalytic subunit alpha 2; RAB: member RAS oncogene family; RPTOR: regulatory associated protein of MTOR complex 1; SCD: stearoyl-CoA desaturase; SIRT1: sirtuin 1; SIRT3: sirtuin 3; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1;SREBF2: sterol regulatory element binding transcription factor 2; STING1: stimulator of interferon response cGAMP interactor 1; STX17: syntaxin 17; TAGs: triacylglycerols; TFEB: transcription factor EB; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VMP1: vacuole membrane protein 1...

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Although physiological responses to the thermal environment are most frequently investigated using constant temperatures, the incorporation of thermal variability can allow for a more accurate prediction of how thermally sensitive species respond to a rapidly changing climate. In species with temperature-dependent sex determination (TSD), developmental responses to incubation temperature are mediated by several genes involved in gonadal differentiation. Kdm6b and Dmrt1 respond to cool incubation temperatures and are associated with testis development, while Foxl2 and Cyp19A1 respond to warm incubation temperatures and are associated with ovary development...

Glioblastoma (GBM) tumors are enriched in immune-suppressive myeloid cells and are refractory to immune checkpoint therapy (ICT). Targeting epigenetic pathways to reprogram the functional phenotype of immune-suppressive myeloid cells to overcome resistance to ICT remains unexplored. Single-cell and spatial transcriptomic analyses of human GBM tumors demonstrated high expression of an epigenetic enzyme-histone 3 lysine 27 demethylase (KDM6B)-in intratumoral immune-suppressive myeloid cell subsets...

Dermal Fibroblast Progenitors (DFPs) differentiate into distinct fibroblast lineages during skin development. However, the epigenetic mechanisms that regulate DFP differentiation are not known. Our objective was to use multimodal single-cell approaches, epigenetic assays, and allografting techniques to define a DFP state and the mechanism that governs its differentiation potential. Our initial results indicated that the overall transcription profile of DFPs is repressed by H3K27me3 and has inaccessible chromatin at lineage-specific genes...

miR-146b-5p has been studied to be highly expressed in bronchopulmonary dysplasia (BPD), but whether it is involved in regulating the process of BPD in premature infants remains unclear. This study was to explore miR-146b-5p in premature BPD and reveal its molecular mechanism. BPD mouse model and high-oxygen MLE-12 cell model were established. HE staining, TUNEL staining, and IF staining were conducted to evaluate the pathological injury and protein expression in mouse lung tissue. LDH assay, MMT assay, and flow cytometry were achieved to evaluate cytotoxicity, cell viability, and apoptosis...

Aberrant epigenetic modifications or events regulate autophagy to influence tumor progression, which has gained increasing attention. KDM6B is an essential histone demethylase that participates in multiple processes of tumors, but its role in thyroid carcinoma (THCA) remains to be unknown. Here, in this study, we used the MTT assay to screen and validate that KDM6B is an essential demethylase for THCA. KDM6B promotes THCA proliferation, migration, invasion in vitro and in vivo. Transcriptional factor E2F1 directly binds to the promoter region of KDM6B and regulates its mRNA levels in THCA...

Multiple signaling pathways facilitate the survival and drug resistance of malignant B-cells by regulating their migration and adhesion to microenvironmental niches. NF-κB pathways are commonly dysregulated in mantle cell lymphoma (MCL), but the exact underlying mechanisms are not well understood. Here, using a co-culture model system, we show that the adhesion of MCL cells to stromal cells is associated with elevated levels of KDM6B histone demethylase mRNA in adherent cells. The inhibition of KDM6B activity, using either a selective inhibitor (GSK-J4) or siRNA-mediated knockdown, reduces MCL adhesion to stromal cells...

Considering that humans are unavoidably exposed to triazole fungicides through the esophagus, respiratory tract, and skin contact, revealing the developmental toxicity of triazole fungicides is vital for health risk assessment. This study aimed to screen and discriminate neural developmental disorder chemicals in commonly used triazole fungicides, and explore the underlying harmful impacts on neurogenesis associated with histone modification abnormality in mouse embryonic stem cells (mESCs). The triploblastic and neural differentiation models were constructed based on mESCs to expose six typical triazole fungicides (myclobutanil, tebuconazole, hexaconazole, propiconazole, difenoconazole, and flusilazole)...

(1) Background: There is an urgent need for effective treatments for cocaine use disorder (CUD), and new pharmacological approaches targeting epigenetic mechanisms appear to be promising options for the treatment of this disease. Dopamine Transporter (DAT) transgenic rats recently have been proposed as a new animal model for studying susceptibility to CUD. (2) Methods: DAT transgenic rats were treated chronically with cocaine (10 mg/kg) for 8 days, and the expression of epigenetic modulators, Lysine Demethylase 6B (KDM6B) and Bromodomain-containing protein 4 (BRD4), was examined in the prefrontal cortex (PFC)...

Coronavirus disease 2019 (COVID-19) is raging worldwide and causes an immense disease burden. Despite this, the biomarkers and targeting drugs of COVID-19 of differing severity remain largely unknown. Based on the GSE164805 dataset, we identified modules most critical for mild COVID-19 (mCOVID-19) and severe COVID-19 (sCOVID-19) through WGCNA, respectively. We subsequently constructed a protein-protein interaction network, and detected 16 hub genes for mCOVID-19 and 10 hub genes for sCOVID-19, followed by the prediction of upstream transcription factors (TFs) and kinases...

Fibrosis, or excessive scarring, is characterized by the emergence of alpha-smooth muscle actin (αSMA)-expressing myofibroblasts and the excessive accumulation of fibrotic extracellular matrix (ECM). Currently, there is a lack of effective treatment options for fibrosis, highlighting an unmet need to identify new therapeutic targets. The acquisition of a fibrotic phenotype is associated with changes in chromatin structure, a key determinant of gene transcription activation and repression. The major repressive histone mark, H3K27me3, has been linked to dynamic changes in gene expression in fibrosis through alterations in chromatin structure...

Stem cells from the apical papilla (SCAPs) are used to regulate the microenvironment of nerve defects. KDM6B, which functions as an H3K27me3 demethylase, is known to play a crucial role in neurogenesis. However, the mechanism by which KDM6B influences the neurogenesis potential of SCAPs remains unclear. We evaluated the expression of neural markers in SCAPs by using real-time RT-PCR and immunofluorescence staining. To assess the effectiveness of SCAP transplantation in the SCI model, we used the BBB scale to evaluate motor function...

Epigenetic reprogramming during fertilization and somatic cell nuclear transfer (NT) is required for cell plasticity and competent development. Here, we characterize the epigenetic modification pattern of H4K20me3, a repressive histone signature in heterochromatin, during fertilization and NT reprogramming. Importantly, the dynamic H4K20me3 signature identified during preimplantation development in fertilized embryos differed from NT and parthenogenetic activation (PA) embryos. In fertilized embryos, only maternal pronuclei carried the canonical H4K20me3 peripheral nucleolar ring-like signature...

AIMS: Lysine-specific demethylase 6B (KDM6B) serves as a key mediator of gene transcription. It regulates expression of proinflammatory cytokines and chemokines in variety of diseases. Herein, the role and the underlying mechanisms of KDM6B in inflammatory pain were studied. METHODS: The inflammatory pain was conducted by intraplantar injection of complete Freund's adjuvant (CFA) in rats. Immunofluorescence, Western blotting, qRT-PCR, and chromatin immunoprecipitation (ChIP)-PCR were performed to investigate the underlying mechanisms...

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) can be described as a debilitating lung disease that is characterized by the complex interactions between various immune cell types and signaling pathways. Chromatin-modifying enzymes are significantly involved in regulating gene expression during immune cell development, yet their role in IPF is not well understood. METHODS: In this study, differential gene expression analysis and chromatin-modifying enzyme-related gene data were conducted to identify hub genes, common pathways, immune cell infiltration, and potential drug targets for IPF...

KDM6A (UTX) and KDM6B (JMJD3) are human non-heme Fe(II) and 2-oxoglutarate (2OG) dependent JmjC oxygenases that catalyze the demethylation of trimethylated lysine 27 in the N-terminal tail of histone H3, a post-translational modification that regulates transcription. We performed Combined Quantum Mechanics/ Molecular Mechanics and Molecular Dynamics study on the catalytic mechanism of KDM6A/B. The results reveal that the transition state for the rate-limiting hydrogen atom transfer (HAT) reaction in KDM6A/B catalysis is stabilized by polar (Asn217) and aromatic (Trp369)/non-polar (Pro274) residues in contrast to KDM4 and KDM7 demethylases where charged residues (Glu, Arg, Asp) are involved...

Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive emergence of myofibroblasts. In the early stages of myofibroblast precursor cell differentiation, we discovered that H3K27me3 demethylase enzymes UTX/KDM6B creates a delay in the accumulation of H3K27me3 on nascent DNA revealing a period of decondensed chromatin structure ...