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1.
Nat Commun ; 11(1): 4639, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934238

RESUMO

The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPRmt) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPRmt. HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPRmt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPRmt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/enzimologia , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Histona Desacetilases/metabolismo , Longevidade , Mitocôndrias/enzimologia , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/genética , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Histona Desacetilases/genética , Macaca mulatta , Estresse Fisiológico , Resposta a Proteínas não Dobradas
2.
Nat Commun ; 11(1): 3822, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732898

RESUMO

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.


Assuntos
Histona Desacetilases/genética , Homeostase/genética , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Animais , Apoptose/genética , Diferenciação Celular/genética , Linhagem Celular , Células Cultivadas , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Ontologia Genética , Histona Desacetilases/deficiência , Histona Desacetilases/metabolismo , Pulmão/embriologia , Pulmão/crescimento & desenvolvimento , Macrófagos Alveolares/citologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
3.
Nat Commun ; 11(1): 3841, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737323

RESUMO

Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets in cancer biology. Whilst it has been established that HDACs regulate many cellular processes, far less is known about the regulation of these enzymes themselves. Here, we show that HDAC8 is allosterically regulated by shifts in populations between exchanging states. An inactive state is identified, which is stabilised by a range of mutations and resembles a sparsely-populated state in equilibrium with active HDAC8. Computational models show that the inactive and active states differ by small changes in a regulatory region that extends up to 28 Å from the active site. The regulatory allosteric region identified here in HDAC8 corresponds to regions in other class I HDACs known to bind regulators, thus suggesting a general mechanism. The presented results pave the way for the development of allosteric HDAC inhibitors and regulators to improve the therapy for several disease states.


Assuntos
Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Ácidos Hidroxâmicos/química , Indóis/química , Proteínas Repressoras/química , Vorinostat/química , Regulação Alostérica , Sítio Alostérico , Domínio Catalítico , Clonagem Molecular , Cristalografia por Raios X , Ativação Enzimática , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/metabolismo , Indóis/metabolismo , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Especificidade por Substrato , Termodinâmica , Vorinostat/metabolismo
4.
Nat Commun ; 11(1): 4154, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32814778

RESUMO

The DNA damage response (DDR) coordinates DNA metabolism with nuclear and non-nuclear processes. The DDR kinase Rad53CHK1/CHK2 controls histone degradation to assist DNA repair. However, Rad53 deficiency causes histone-dependent growth defects in the absence of DNA damage, pointing out unknown physiological functions of the Rad53-histone axis. Here we show that histone dosage control by Rad53 ensures metabolic homeostasis. Under physiological conditions, Rad53 regulates histone levels through inhibitory phosphorylation of the transcription factor Spt21NPAT on Ser276. Rad53-Spt21 mutants display severe glucose dependence, caused by excess histones through two separable mechanisms: dampening of acetyl-coenzyme A-dependent carbon metabolism through histone hyper-acetylation, and Sirtuin-mediated silencing of starvation-induced subtelomeric domains. We further demonstrate that repression of subtelomere silencing by physiological Tel1ATM and Rpd3HDAC activities coveys tolerance to glucose restriction. Our findings identify DDR mutations, histone imbalances and aberrant subtelomeric chromatin as interconnected causes of glucose dependence, implying that DDR kinases coordinate metabolism and epigenetic changes.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , Glucose/metabolismo , Histonas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/genética , Quinase do Ponto de Checagem 2/genética , Dano ao DNA , Reparo do DNA , Inativação Gênica , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Serina/genética , Serina/metabolismo , Telômero/genética , Fatores de Transcrição/genética
5.
PLoS Pathog ; 16(8): e1008802, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32822428

RESUMO

Hepatitis B virus (HBV) is a worldwide health problem without curative treatments. Investigation of the regulation of HBV biosynthesis by class I and II histone deacetylases (HDACs) demonstrated that catalytically active HDAC5 upregulates HBV biosynthesis. HDAC5 expression increased both the stability and splicing of the HBV 3.5 kb RNA without altering the translational efficiency of the viral pregenomic or spliced 2.2 kb RNAs. Together, these observations point to a broader role of HDAC5 in regulating RNA splicing and transcript stability while specifically identifying a potentially novel approach toward antiviral HBV therapeutic development.


Assuntos
Genoma Viral , Vírus da Hepatite B/metabolismo , Hepatite B/virologia , Histona Desacetilases/metabolismo , Estabilidade de RNA , RNA Viral/biossíntese , RNA Viral/química , Regulação Viral da Expressão Gênica , Células Hep G2 , Vírus da Hepatite B/genética , Histona Desacetilases/genética , Humanos , Transcrição Genética , Replicação Viral
6.
Gene ; 757: 144928, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32622989

RESUMO

Tassel branch number (TBN) is the principal component of tassel inflorescence architecture in the maize plant. TBN is believed to be controlled by a set of quantitative trait loci (QTLs). However, it is necessary to identify and genetically evaluate these QTLs before the TBN can be improved upon using a molecular breeding approach. Therefore, in this study, we developed the chromosome segment introgression line (CSIL) TBN1 with the Zong31 (Z31) background and a higher TBN, and then we utilized the CSIL-TBN1-derived populations and identified a major QTL, qTBN6a, by linkage analysis. Fine mapping of the qTBN6a QTL was validated using a set of sub-CSILs and located in a 240-kb genomic region (Bin6.07) in B73RefGen_v4. One allele included in the introgression fragment had a positive effect, noticeably increasing the TBN and demonstrating the potential to improve the TBN of Z31. Afterward, in the qTBN6a interval, gene expression, sequence alignment, functional analysis, and the analysis of motifs in the 5' UTR suggested that candidate genes of qTBN6a are important functional genes at the early stage of immature infected tassel development. Among these candidate genes, a long W22::Mu-insertion/deletion in exon one and an 11-bp insertion/deletion in the promoter region may affect the variation of the qTBN6a QTL observed between Z31 and TBN1. In addition, the candidate genes of qTBN6a were found to encode a pentatricopeptide repeat (PPR)-containing protein and a histone deacetylase (HDA), which are known to be closely associated with RNA editing and stability and chromatin state activity for the transcription of gene expression, respectively. Finally, a model of qTBN6a based on the synergistic regulation of PPR and HDA for the maintenance of inflorescence meristem (IM) identity and its differentiation to the branch meristem (BM) in TBN1 was suggested. Collectively, our results provide an available locus for the molecular improvement of TBN and the isolation of functional genes underlying this QTL.


Assuntos
Meristema/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Zea mays/genética , Genoma de Planta , Histona Desacetilases/genética , Meristema/crescimento & desenvolvimento , Proteínas de Plantas/genética , Zea mays/crescimento & desenvolvimento
7.
Plant Mol Biol ; 104(1-2): 67-79, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621165

RESUMO

Acetylation and deacetylation of histones are important for regulating a series of biological processes in plants. Histone deacetylases (HDACs) control the histone deacetylation that plays an important role in plant response to abiotic stress. In our study, we show the evidence that GhHDT4D (a member of the HD2 subfamily of HDACs) is involved in cotton (Gossypium hirsutum) response to drought stress. Overexpression of GhHDT4D in Arabidopsis increased plant tolerance to drought, whereas silencing GhHDT4D in cotton resulted in plant sensitivity to drought. Simultaneously, the H3K9 acetylation level was altered in the GhHDT4D silenced cotton, compared with the controls. Further study revealed that GhHDT4D suppressed the transcription of GhWRKY33, which plays a negative role in cotton defense to drought, by reducing its H3K9 acetylation level. The expressions of the stress-related genes, such as GhDREB2A, GhDREB2C, GhSOS2, GhRD20-1, GhRD20-2 and GhRD29A, were significantly decreased in the GhHDT4D silenced cotton, but increased in the GhWRKY33 silenced cotton. Given these data together, our findings suggested that GhHDT4D may enhance drought tolerance by suppressing the expression of GhWRKY33, thereby activating the downstream drought response genes in cotton.


Assuntos
Secas , Gossypium/metabolismo , Histona Desacetilases/metabolismo , Estresse Fisiológico/fisiologia , Acetilação , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Inativação Gênica , Gossypium/genética , Histona Desacetilases/genética , Histonas/genética , Histonas/metabolismo , Filogenia , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas , Estresse Fisiológico/genética , Transcriptoma
8.
Nat Commun ; 11(1): 3282, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32612176

RESUMO

Osteocytes, cells ensconced within mineralized bone matrix, are the primary skeletal mechanosensors. Osteocytes sense mechanical cues by changes in fluid flow shear stress (FFSS) across their dendritic projections. Loading-induced reductions of osteocytic Sclerostin (encoded by Sost) expression stimulates new bone formation. However, the molecular steps linking mechanotransduction and Sost suppression remain unknown. Here, we report that class IIa histone deacetylases (HDAC4 and HDAC5) are required for loading-induced Sost suppression and bone formation. FFSS signaling drives class IIa HDAC nuclear translocation through a signaling pathway involving direct HDAC5 tyrosine 642 phosphorylation by focal adhesion kinase (FAK), a HDAC5 post-translational modification that controls its subcellular localization. Osteocyte cell adhesion supports FAK tyrosine phosphorylation, and FFSS triggers FAK dephosphorylation. Pharmacologic FAK catalytic inhibition reduces Sost mRNA expression in vitro and in vivo. These studies demonstrate a role for HDAC5 as a transducer of matrix-derived cues to regulate cell type-specific gene expression.


Assuntos
Proteína-Tirosina Quinases de Adesão Focal/genética , Histona Desacetilases/genética , Mecanotransdução Celular/genética , Osteócitos/metabolismo , Transdução de Sinais/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Perfilação da Expressão Gênica/métodos , Histona Desacetilases/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteogênese/genética , Fosforilação
9.
Mol Carcinog ; 59(8): 955-966, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32391971

RESUMO

Maspin repression is frequently observed in prostate cancer; however, the molecular mechanism(s) causing the loss is not completely understood. Here, we demonstrate that inhibition of class I histone deacetylases (HDACs) mediates re-expression of maspin which plays an essential role in suppressing proliferation and migration capability in prostate cancer cells. Human prostate cancer LNCaP and DU145 cells treated with HDAC inhibitors, sodium butyrate, and trichostatin A, resulted in maspin re-expression. Interestingly, an exploration into the molecular mechanisms demonstrates that maspin repression in prostate tumor and human prostate cancer cell lines occurs via epigenetic silencing through an increase in HDAC activity/expression, independent of promoter DNA hypermethylation. Furthermore, transcriptional activation of maspin was accompanied with the suppression of HDAC1 and HDAC8 with significant p53 enrichment at the maspin promoter associated with an increase in histone H3/H4 acetylation. Our results provide evidence of maspin induction as a critical epigenetic event altered by class I HDACs in the restoration of balance to delay proliferation and migration ability of prostate cancer cells.


Assuntos
Biomarcadores Tumorais/metabolismo , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/metabolismo , Neoplasias da Próstata/patologia , Serpinas/genética , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Epigênese Genética , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Histona Desacetilases/genética , Histonas , Humanos , Ácidos Hidroxâmicos/farmacologia , Masculino , Prognóstico , Regiões Promotoras Genéticas , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Serpinas/metabolismo , Células Tumorais Cultivadas
10.
Life Sci ; 252: 117637, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32251633

RESUMO

BACKGROUND: Berberine plays a neuroprotective role in neurodegenerative diseases, including Alzheimer's disease (AD). Circular RNAs (circRNAs) function as crucial players in AD pathogenesis. In the current work, we aimed to investigate whether circRNA histone deacetylase 9 (circHDAC9) was involved in the regulation of berberine in AD. METHODS: Cell viability and apoptosis were determined by the Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. Enzyme-linked immunosorbent assay (ELISA) was used to assess caspase-3 activity and the production of interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α). The levels of circHDAC9 and miR-142-5p were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Subcellular fractionation assays were performed to evaluate the localization of circHDAC9. The direct interaction between circHDAC9 and miR-142-5p was confirmed by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays. RESULTS: Our data indicated that circHDAC9 was indeed a circular transcript and mainly localized in the cytoplasm. 42-residue ß-amyloid (Aß42) triggered a significant down-regulation in circHDAC9 and a striking up-regulation in miR-142-5p in human neuronal (HN) cells. Berberine relieved Aß42-induced HN cell neurotoxicity. Moreover, berberine resulted in increased circHDAC9 expression and decreased miR-142-5p level in Aß42-treated HN cells. Berberine alleviated Aß42-induced neuronal damage in HN cells by up-regulating circHDAC9. Furthermore, circHDAC9 acted as a molecular sponge of miR-142-5p. CircHDAC9 overexpression alleviated Aß42-induced HN cell neurotoxicity via miR-142-5p. CONCLUSION: Our current study suggested that berberine protected HN cell from Aß42-induced neuronal damage at least partly through regulating the circHDAC9/miR-142-5p axis, highlighting novel evidence for the neuroprotective effect of berberine in AD.


Assuntos
Berberina/farmacologia , Histona Desacetilases/genética , MicroRNAs/genética , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas Repressoras/genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/toxicidade , Apoptose/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Humanos , Neurônios/patologia , Fragmentos de Peptídeos/toxicidade , RNA Circular/genética , Regulação para Cima
11.
Zhonghua Zhong Liu Za Zhi ; 42(3): 197-202, 2020 Mar 23.
Artigo em Chinês | MEDLINE | ID: mdl-32252197

RESUMO

Objective: To investigate the effects of metastasis associated gene 1 (MTA1) expression on the proliferation and apoptosis of human esophageal cancer Eca109 cells. Methods: MTA1 siRNA was transfected into human esophageal cancer Eca109 cells, and the control group and blank group were set up. The expression of MTA1 in Eca109 cells with different treatment was detected by real-time fluorescent quantitative PCR (RT-PCR) and western blot. The proliferation of Eca109 cells was detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) assay. The cloning formation ability of Eca109 cells was detected by plate cloning assay. The apoptosis of Eca109 cells were detected by flow cytometry. The expression of proliferating cell nuclear antigen (PCNA) and apoptosis-related proteins, including cleaved caspase-3 and total caspase-3 protein in Eca109 cells were detected by western blot. Results: After 48 hours of transfection, RT-PCR result showed that the relative expression levels of MTA1 mRNA in Eca109 cells in the blank group, control group, and siRNA group were 1.00±0.10, 0.98±0.09 and 0.21±0.03, respectively. The expression of MTA1 mRNA in siRNA group was significantly inhibited (P<0.05), while no significant difference of MTA1 mRNA expression between the blank group and the control group has been found (P>0.05). Western blot results were consistent with those of RT-PCR. MTT array results showed that, compared with the blank group and transfection group, the absorbance values of Eca109 cells in siRNA group were dramatically reduced at 48, 72, and 96 h (all P<0.05). There were no significant differences of absorbance values between the blank group and the control group at 48, 72, and 96 h (all P>0.05). The results of the plate colony formation test showed that the number of colony formation in the blank group and control group were 58.64±6.86 and 60.02±7.04, respectively, significantly higher than 18.10±3.16 in siRNA group (P<0.05), while there was no significant difference between the blank group and control group (P>0.05). Flow cytometry results showed that the apoptosis rates in the blank group and control group were (2.13±0.54)% and (2.27±0.61)%, respectively, significantly lower than (32.61±5.28)% in siRNA group (P<0.05), while there was no significant difference between blank group and control group (P>0.05). Western blot results showed that the expression of PCNA protein was down-regulated while cleaved caspase-3 protein expression was upregulated in siRNA group, compared to the control group and blank group (P<0.05). Conclusions: Inhibition of MTA1 expression can inhibit the proliferation of Eca109 cells and induce apoptosis. This process may be related to the down-regulation of PCNA protein expression and activation of caspase-3 protein expression.


Assuntos
Apoptose , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/fisiologia , Proteínas Repressoras/fisiologia , Transativadores/metabolismo , Apoptose/genética , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Esofágicas/metabolismo , Histona Desacetilases/genética , Humanos , Antígeno Nuclear de Célula em Proliferação , RNA Interferente Pequeno/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transativadores/genética , Transfecção
12.
PLoS Biol ; 18(4): e3000220, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32315298

RESUMO

Many lines of evidence point to links between sleep regulation and energy homeostasis, but mechanisms underlying these connections are unknown. During Caenorhabditis elegans sleep, energetic stores are allocated to nonneural tasks with a resultant drop in the overall fat stores and energy charge. Mutants lacking KIN-29, the C. elegans homolog of a mammalian Salt-Inducible Kinase (SIK) that signals sleep pressure, have low ATP levels despite high-fat stores, indicating a defective response to cellular energy deficits. Liberating energy stores corrects adiposity and sleep defects of kin-29 mutants. kin-29 sleep and energy homeostasis roles map to a set of sensory neurons that act upstream of fat regulation as well as of central sleep-controlling neurons, suggesting hierarchical somatic/neural interactions regulating sleep and energy homeostasis. Genetic interaction between kin-29 and the histone deacetylase hda-4 coupled with subcellular localization studies indicate that KIN-29 acts in the nucleus to regulate sleep. We propose that KIN-29/SIK acts in nuclei of sensory neuroendocrine cells to transduce low cellular energy charge into the mobilization of energy stores, which in turn promotes sleep.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Sono/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Núcleo Celular/metabolismo , Metabolismo Energético/genética , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Mutação , Células Neuroendócrinas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Células Receptoras Sensoriais/metabolismo
13.
PLoS One ; 15(3): e0229241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119686

RESUMO

While genome-wide association studies have identified genes involved in differential treatment responses to inhaled corticosteroids (ICS) in asthma, few studies have evaluated the potential effects of age in this context. A significant proportion of asthmatics experience exacerbations (hospitalizations and emergency department visits) during ICS treatment. We evaluated the interaction of genetic variation and age on ICS response (measured by the occurrence of exacerbations) through a genome-wide interaction study (GWIS) of 1,321 adult and child asthmatic patients of European ancestry. We identified 107 genome-wide suggestive (P<10-05) age-by-genotype interactions, two of which also met genome-wide significance (P<5x10-08) (rs34631960 [OR 2.3±1.6-3.3] in thrombospondin type 1 domain-containing protein 4 (THSD4) and rs2328386 [OR 0.5±0.3-0.7] in human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2)) by joint analysis of GWIS results from discovery and replication populations. In addition to THSD4 and HIVEP2, age-by-genotype interactions also prioritized genes previously identified as asthma candidate genes, including DPP10, HDAC9, TBXAS1, FBXL7, and GSDMB/ORMDL3, as pharmacogenomic loci as well. This study is the first to link these genes to a pharmacogenetic trait for asthma.


Assuntos
Corticosteroides/administração & dosagem , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Proteínas ADAM/genética , Administração por Inalação , Adolescente , Corticosteroides/uso terapêutico , Adulto , Fatores Etários , Idoso , Antiasmáticos/uso terapêutico , Asma/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Serviço Hospitalar de Emergência , Feminino , Estudo de Associação Genômica Ampla , Histona Desacetilases/genética , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Resultado do Tratamento , Adulto Jovem
14.
Proc Natl Acad Sci U S A ; 117(12): 6509-6520, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32152128

RESUMO

Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína p300 Associada a E1A/metabolismo , Regulação da Expressão Gênica , Histona Desacetilases/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Elongação da Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Sítios de Ligação , Linhagem Celular , Diabetes Mellitus Tipo 2/patologia , Proteína p300 Associada a E1A/genética , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Histona Desacetilases/genética , Humanos , Leucócitos Mononucleares/metabolismo , Mutação , Ligação Proteica , Estabilidade Proteica , Transcrição Genética , Fatores de Elongação da Transcrição/química , Fatores de Elongação da Transcrição/genética , Ubiquitinação
15.
Gene ; 739: 144512, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32112983

RESUMO

Pleckstrin homology-like domain family A member 2 (PHLDA2) is essential for placental development in mammals. This study was conducted to investigate transcriptional regulation of goat PHLDA2 in the placenta. Real-time PCR and Western blot analyses showed different expression of the PHLDA2 in goat placentas during gestation with highest expression at 30 and 45 days post coitus (P < 0.05). Luciferase reporter assays demonstrated the highest promoter activity in the region of -1023/+20 (P < 0.05). A CpG island was defined within -631/+379 region, where lower level of CpG-methylation was detected with bisulfite sequencing PCR in the placenta than that in the spleen and liver (P < 0.05). Meanwhile, in vitro experiments showed that 5-AzaC enhanced the gene expression in a dose-dependent manner. Site-directed mutation in vitro demonstrated that transcription factor Ying-yang 1 (YY1) had an inhibitory effect on the PHLDA2 expression, and the inhibition was further confirmed with overexpression and siRNA constructs of YY1. ChIP and RE-ChIP analyses further identified the binding of YY1 to the PHLDA2 promoter by interaction with histone deacetylase 1 (HDAC1) and HDAC3. This study uncovers the negative regulation of the CpG-methylation and YY1 on goat PHLDA2 expression. YY1 prefers binding to CpG-methylation sequences, and inhibits goat PHLDA2 expression via recruiting HDAC1 and 3.


Assuntos
Regulação da Expressão Gênica , Cabras/genética , Histona Desacetilase 1/metabolismo , Histona Desacetilases/metabolismo , Proteínas Nucleares/metabolismo , Fator de Transcrição YY1/metabolismo , Animais , Ilhas de CpG/genética , Metilação de DNA , Feminino , Histona Desacetilase 1/genética , Histona Desacetilases/genética , Proteínas Nucleares/genética , Placenta , Gravidez , Regiões Promotoras Genéticas/genética , Fator de Transcrição YY1/genética
16.
Nucleic Acids Res ; 48(6): 3089-3102, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32030426

RESUMO

Long non-coding RNAs (lncRNAs) have emerged as important biological tuners. Here, we reveal the role of an uncharacterized lncRNA we call SENEBLOC that is expressed by both normal and transformed cells under homeostatic conditions. SENEBLOC was shown to block the induction of cellular senescence through dual mechanisms that converge to repress the expression of p21. SENEBLOC facilitates the association of p53 with MDM2 by acting as a scaffold to promote p53 turnover and decrease p21 transactivation. Alternatively, SENEBLOC was shown to affect epigenetic silencing of the p21 gene promoter through regulation of HDAC5. Thus SENEBLOC drives both p53-dependent and p53-independent mechanisms that contribute to p21 repression. Moreover, SENEBLOC was shown to be involved in both oncogenic and replicative senescence, and from the perspective of senolytic agents we show that the antagonistic actions of rapamycin on senescence are dependent on SENEBLOC expression.


Assuntos
Envelhecimento/genética , Neoplasias/genética , RNA Longo não Codificante/genética , Proteína Supressora de Tumor p53/genética , Animais , Carcinogênese/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Xenoenxertos , Histona Desacetilases/genética , Humanos , Camundongos , Ligação Proteica/genética , Transdução de Sinais/genética
17.
PLoS One ; 15(2): e0229283, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084202

RESUMO

Necrotizing enterocolitis (NEC) is a devastating intestinal emergency that affects ten percent of very low birth weight premature babies and costs society in both expense and heartache. It is probably caused by an inappropriate interaction of colonizing bacteria with an immature intestine. A possible preventative measure is to feed prematures their mother's expressed breast milk in conjunction with a probiotic. This synbiotic prevention reduces the severity and incidence of this condition. This study was designed to determine the mechanism of the synbiotic effect in human and mouse fetal intestine. Breast milk interacting with a NEC preventative probiotic such as Bifidobacterium infantis can produce increased levels of short chain fatty acids (acetate, propionate and butyrate) (SCFAs). SCFAs are known to be anti-inflammatory in mature enterocytes and immunocytes. Very little is known about their role in immature intestine. When exposed to a human fetal cell line, fetal intestinal organoids and fetal mouse intestine, these SCFAs were anti-inflammatory. Their mechanism of anti-inflammation differed from those reported for mature cells by involving the G-protein coupled receptor (GPR 109A) and inhibiting histone deacetylase 4 and 5. These bacterial metabolites may help explain the synbiotic anti-inflammatory effect of breast milk and probiotics given to premature infants at risk for NEC.


Assuntos
Bifidobacterium longum subspecies infantis/fisiologia , Enterócitos/citologia , Enterócitos/efeitos dos fármacos , Ácidos Graxos Voláteis/biossíntese , Ácidos Graxos Voláteis/farmacologia , Intestinos/microbiologia , Leite Humano/microbiologia , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Enterócitos/metabolismo , Indução Enzimática/efeitos dos fármacos , Feto/microbiologia , Histona Desacetilases/genética , Humanos , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Intestinos/citologia , Camundongos , Mutagênese Insercional/efeitos dos fármacos , Organoides/efeitos dos fármacos , Organoides/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
18.
Life Sci ; 248: 117469, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32109485

RESUMO

AIMS: Histone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying molecular mechanisms. MAIN METHODS: MTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the molecular mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 subcutaneous tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects. KEY FINDINGS: Our results demonstrated that SB939 at 0.5-1 µmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models. SIGNIFICANCE: Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Vimentina/genética , Vimentina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Cell ; 180(5): 928-940.e14, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32109413

RESUMO

Covalent modifications to histones are essential for development, establishing distinct and functional chromatin domains from a common genetic sequence. Whereas repressed chromatin is robustly inherited, no mechanism that facilitates inheritance of an activated domain has been described. Here, we report that the Set3C histone deacetylase scaffold Snt1 can act as a prion that drives the emergence and transgenerational inheritance of an activated chromatin state. This prion, which we term [ESI+] for expressed sub-telomeric information, is triggered by transient Snt1 phosphorylation upon cell cycle arrest. Once engaged, the prion reshapes the activity of Snt1 and the Set3C complex, recruiting RNA pol II and interfering with Rap1 binding to activate genes in otherwise repressed sub-telomeric domains. This transcriptional state confers broad resistance to environmental stress, including antifungal drugs. Altogether, our results establish a robust means by which a prion can facilitate inheritance of an activated chromatin state to provide adaptive benefit.


Assuntos
Cromatina/genética , Histona Desacetilases/genética , Proteínas Nucleares/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Ligação a Telômeros/genética , Fatores de Transcrição/genética , Pontos de Checagem do Ciclo Celular/genética , Código das Histonas/genética , Histonas/genética , Fosforilação/genética , Príons/genética , RNA Polimerase II/genética , Saccharomyces cerevisiae , Telômero/genética , Transcrição Genética
20.
Nat Microbiol ; 5(4): 570-583, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32094587

RESUMO

Toxoplasma gondii has a complex life cycle that is typified by asexual development that takes place in vertebrates, and sexual reproduction, which occurs exclusively in felids and is therefore less studied. The developmental transitions rely on changes in the patterns of gene expression, and recent studies have assigned roles for chromatin shapers, including histone modifications, in establishing specific epigenetic programs for each given stage. Here, we identified the T. gondii microrchidia (MORC) protein as an upstream transcriptional repressor of sexual commitment. MORC, in a complex with Apetala 2 (AP2) transcription factors, was shown to recruit the histone deacetylase HDAC3, thereby impeding the accessibility of chromatin at the genes that are exclusively expressed during sexual stages. We found that MORC-depleted cells underwent marked transcriptional changes, resulting in the expression of a specific repertoire of genes, and revealing a shift from asexual proliferation to sexual differentiation. MORC acts as a master regulator that directs the hierarchical expression of secondary AP2 transcription factors, and these transcription factors potentially contribute to the unidirectionality of the life cycle. Thus, MORC plays a cardinal role in the T. gondii life cycle, and its conditional depletion offers a method to study the sexual development of the parasite in vitro, and is proposed as an alternative to the requirement of T. gondii infections in cats.


Assuntos
Adenosina Trifosfatases/genética , Histona Desacetilases/genética , Histonas/metabolismo , Proteínas de Protozoários/genética , Toxoplasma/genética , Fatores de Transcrição/genética , Transcrição Genética , Adenosina Trifosfatases/química , Adenosina Trifosfatases/metabolismo , Animais , Gatos , Cromatina , Fibroblastos/parasitologia , Código das Histonas , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Histonas/genética , Humanos , Estágios do Ciclo de Vida/genética , Modelos Moleculares , Cultura Primária de Células , Ligação Proteica , Processamento de Proteína Pós-Traducional , Estrutura Secundária de Proteína , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Toxoplasma/crescimento & desenvolvimento , Toxoplasma/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
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