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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 720-723, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302920

RESUMO

OBJECTIVE: To explore the genetic cause of a neonate with congenital dysplasia, growth retardation through clinical evaluation, laboratory tests and next generation sequencing (NGS). METHODS: Peripheral blood samples were obtained from the child and his parents. Whole genomic DNA was extracted and subjected to NGS. Suspected mutation was predicted by bioinformatic tools and validated by Sanger sequencing. RESULTS: The child was found to carry a c.556G>A (p.E186K) mutation of the HDAC8 gene on the X chromosome, which was predicted to be pathogenic by Bioinformatic analysis. CONCLUSION: The patient was diagnosed as Cornelia de Lange syndrome 5 caused by the c.556G>A mutation of the HDAC8 gene.


Assuntos
Síndrome de Lange/genética , Histona Desacetilases/genética , Proteínas Repressoras/genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Masculino , Mutação
2.
Toxicol Lett ; 314: 63-74, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31306741

RESUMO

This study aimed to verify the toxic effects of prenatal caffeine exposure (PCE) on the podocyte development in male offspring, and to explore the underlying intrauterine programming mechanisms. The pregnant rats were administered with caffeine (30 to 120 mg/kg⋅d) during gestational day (GD) 9 to 20. The male fetus on GD20 and the offspring at postnatal week (PW) 6 and PW28 were sacrificed. The results indicated that PCE caused ultrastructural abnormalities on podocyte, and inhibited the expression of podocyte marker genes such as Nephrin, Wilms tumor 1 (WT1), the histone 3 lysine 9 acetylation (H3K9ac) level in the Kruppel-like factor 4 (KLF4) promoter and its expression in the male offspring from GD20 to PW28. Meanwhile, the expression of glucocorticoid receptor (GR) and histone deacetylase 7 (HDAC7) in the fetus were increased by PCE. In vitro, corticosterone increased GR and HDAC7 whereas reduced the H3K9ac level of KLF4 and KLF4/Nephrin expression. KLF4 over-expression reversed the reduction of Nephrin expression, knockdown of HDAC7 and GR antagonist RU486 partially reversed the inhibitory effects of corticosterone on H3K9ac level and KLF4 expression. In conclusion, PCE caused podocyte developmental toxicity in male offspring, which was associated with corticosterone-induced low-functional programming of KLF4 through GR/HDAC7/H3K9ac pathway.


Assuntos
Cafeína/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Histonas/metabolismo , Nefropatias/induzido quimicamente , Fatores de Transcrição Kruppel-Like/metabolismo , Podócitos/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Acetilação , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Idade Gestacional , Glucocorticoides/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Nefropatias/embriologia , Nefropatias/genética , Nefropatias/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Lisina , Masculino , Exposição Materna , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fenótipo , Podócitos/metabolismo , Podócitos/ultraestrutura , Gravidez , Regiões Promotoras Genéticas , Ratos Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
J Agric Food Chem ; 67(32): 8919-8925, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31334658

RESUMO

Histone deacetylase (HDAC) performs important functions in plant growth and development, including fruit ripening. As a complex biological process, fruit ripening involves the histone acetylation modification of ripening-associated genes. Histone deacetylase genes (HDACs) have been well studied in Arabidopsis and rice, but the biological functions of HDACs in papaya are poorly understood. In the present work, three CpHDACs, belonging to the RPD3/HDA1 subfamily, were identified from papaya and named as CpHDA1, CpHDA2, and CpHDA3. CpHDA1 and CpHDA2 were induced by propylene, while CpHDA3 was propylene-repressed. Moreover, CpHDA3 protein could physically interact with CpERF9 and enhance the transcriptional repression activities of CpERF9 to downstream genes CpPME1, CpPME2 and CpPG5. Histone acetylation levels of CpPME1 and CpPG5 were increased during fruit ripening. Taken together, these results suggested that CpERF9 recruits CpHDA3 to form a histone deacetylase repressor complex to mediate pectin methylesterase and polygalacturonase genes expression during papaya fruit ripening and softening.


Assuntos
Hidrolases de Éster Carboxílico/genética , Carica/metabolismo , Frutas/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas , Histona Desacetilases/metabolismo , Proteínas de Plantas/metabolismo , Poligalacturonase/genética , Fatores de Transcrição/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Carica/genética , Carica/crescimento & desenvolvimento , Frutas/genética , Frutas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Histona Desacetilases/genética , Proteínas de Plantas/genética , Poligalacturonase/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Fatores de Transcrição/genética
5.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 23-28, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078148

RESUMO

In recent years, most related studies have found that chronic hepatitis B virus infection is the main cause of hepatocellular carcinoma (HCC), but the specific pathogenesis is still unclear. To investigate the function of HDAC in hepatocellular carcinoma (HCC), this study used qRT-PCR to determine the expression levels of miR-376a and HDAC9 mNRA in HCC and para-cancerous tissues. The clinical significance of HDAC9 in HCC was assessed in a study cohort containing 37 patients with HCC using immunohistochemistry. The expression level of miR-376a in liver cancer tissues was significantly lower than that in para-cancerous tissues, while the expression level of HDAC9 mRNA in liver cancer tissue was significantly higher than that in para-cancerous tissues. The expression of HDAC9 occurred mainly in the nucleus. There was a significant correlation between tumor differentiation and HDAC9. Survival analysis showed that HCC patients with higher HDAC9 expression had poorer prognosis, and subsequent multivariate analysis showed that HDAC9 expression level was an independent predictor. There was a definite correlation between HDAC9 and the expressions of AFP and Ki67. These results suggest that the expression level of HDAC9 in HCC is abnormally high while the expression level of miR-376a is significantly decreased, indicating that HDAC9 may be a potential prognostic indicator of HCC.


Assuntos
Carcinoma Hepatocelular/enzimologia , Histona Desacetilases/metabolismo , Neoplasias Hepáticas/enzimologia , Proteínas Repressoras/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Proteínas Repressoras/genética , Análise de Sobrevida , alfa-Fetoproteínas/metabolismo
6.
J Med Food ; 22(5): 444-450, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084542

RESUMO

Studies have identified the potential of chemopreventive effects of sulforaphane (SFN); however, the underlying mechanisms of its effect on breast cancer require further elucidation. This study investigated the anticancer effects of SFN that specifically induces G1/S arrest in breast ductal carcinoma (ZR-75-1) cells. The proliferation of the cancer cells after treatment with SFN was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. DNA content and cell cycle status were analyzed through flow cytometry. Our results demonstrated the inhibition of growth in ZR-75-1 cells upon SFN exposure. In addition, SERTAD1 (SEI-1) caused the accumulation of SFN-treated G1/S-phase cells. The downregulation of SEI-1, cyclin D2, and histone deacetylase 3 suggested that in addition to the identified effects of SFN against breast cancer prevention, it may also exert antitumor activities in established breast cancer cells. In conclusion, SFN can inhibit growth of and induce cell cycle arrest in cancer cells, suggesting its potential role as an anticancer agent.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Isotiocianatos/farmacologia , Proteínas Nucleares/genética , Transativadores/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D2/genética , Ciclina D2/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Extratos Vegetais/farmacologia , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Transativadores/metabolismo , Verduras/química
7.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052182

RESUMO

Class I histone deacetylases (HDACs) generally promote cell proliferation and tumorigenesis, whereas class IIA HDACs like HDAC4 and HDAC5 may promote or impede cancer development in a tissue-dependent manner. In urothelial carcinoma (UC), HDAC5 is often downregulated. Accordingly, HDAC5 was weakly expressed in UC cell lines suggesting a possible tumor-suppressive function. We therefore characterized the effects of stable HDAC5 expression in four UC cell lines (RT112, VM-Cub-1, SW1710 and UM-UC-3) with different phenotypes reflecting the heterogeneity of UC, by assessing proliferation, clonogenicity and migration ability. Further, we detailed changes in the proteome and transcriptome by immunoblotting, mass spectrometry and RNA sequencing analysis. We observed that HDAC5 overexpression in general decreased cell proliferation, but in one cell line (VM-Cub-1) induced a dramatic change from an epitheloid to a mesenchymal phenotype, i.e., epithelial-mesenchymal transition (EMT). These phenotypical changes were confirmed by comprehensive proteomics and transcriptomics analyses. In contrast to HDAC5, overexpression of HDAC4 exerted only weak effects on cell proliferation and phenotypes. We conclude that overexpression of HDAC5 may generally decrease proliferation in UC, but, intriguingly, may induce EMT on its own in certain circumstances.


Assuntos
Carcinoma/metabolismo , Proliferação de Células , Transição Epitelial-Mesenquimal , Histona Desacetilases/genética , Neoplasias da Bexiga Urinária/metabolismo , Urotélio/patologia , Carcinoma/genética , Linhagem Celular Tumoral , Células HEK293 , Histona Desacetilases/metabolismo , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias da Bexiga Urinária/genética , Urotélio/metabolismo
8.
Expert Opin Drug Saf ; 18(7): 563-571, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31070945

RESUMO

INTRODUCTION: Dysregulation of histone deacetylase (HDAC) activity is an epigenetic hallmark of multiple myeloma (MM), leading to aberrant gene expression and cellular signaling in myeloma cell growth, survival and resistance to therapy. Hyper-methylation at diagnosis is a frequent observation, which eventually may convert to hypo-methylation during advanced phases. AREAS COVERED: A literature search on 'HDAC inhibitors' and 'multiple myeloma' was carried out using PubMed and Google Scholar in the preparation of this overview on clinical efficacy and safety data. EXPERT OPINION: First-generation non-selective HDAC inhibitors have demonstrated minimal single-agent activity in refractory MM. Subsequently, combination therapy has proven an improvement in progression-free survival (PFS) but not response rates. The main concerns are associated with toxicities. Ongoing studies on new and more selective agents, i.e. Romidepsin or Ricolinostat, are promising in terms of better efficacy and less toxicity.


Assuntos
Antineoplásicos/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases/efeitos adversos , Histona Desacetilases/efeitos dos fármacos , Histona Desacetilases/genética , Humanos , Mieloma Múltiplo/genética , Panobinostat/administração & dosagem , Panobinostat/efeitos adversos , Resultado do Tratamento
9.
Nat Commun ; 10(1): 1566, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30952952

RESUMO

The class 3 phosphoinositide 3-kinase (PI3K) is required for lysosomal degradation by autophagy and vesicular trafficking, assuring nutrient availability. Mitochondrial lipid catabolism is another energy source. Autophagy and mitochondrial metabolism are transcriptionally controlled by nutrient sensing nuclear receptors. However, the class 3 PI3K contribution to this regulation is unknown. We show that liver-specific inactivation of Vps15, the essential regulatory subunit of the class 3 PI3K, elicits mitochondrial depletion and failure to oxidize fatty acids. Mechanistically, transcriptional activity of Peroxisome Proliferator Activated Receptor alpha (PPARα), a nuclear receptor orchestrating lipid catabolism, is blunted in Vps15-deficient livers. We find PPARα repressors Histone Deacetylase 3 (Hdac3) and Nuclear receptor co-repressor 1 (NCoR1) accumulated in Vps15-deficient livers due to defective autophagy. Activation of PPARα or inhibition of Hdac3 restored mitochondrial biogenesis and lipid oxidation in Vps15-deficient hepatocytes. These findings reveal roles for the class 3 PI3K and autophagy in transcriptional coordination of mitochondrial metabolism.


Assuntos
Autofagia/fisiologia , Metabolismo dos Lipídeos , Mitocôndrias/metabolismo , PPAR alfa/metabolismo , Fosfatidilinositol 3-Quinases/fisiologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Fenofibrato/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histona Desacetilases/fisiologia , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Correpressor 1 de Receptor Nuclear/genética , Correpressor 1 de Receptor Nuclear/metabolismo , Correpressor 1 de Receptor Nuclear/fisiologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteína VPS15 de Distribuição Vacuolar/genética , Proteína VPS15 de Distribuição Vacuolar/metabolismo , Proteína VPS15 de Distribuição Vacuolar/fisiologia
10.
Nat Commun ; 10(1): 1713, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979883

RESUMO

Unlike activation of target genes in response to abscisic acid (ABA), how MYB96 transcription factor represses ABA-repressible genes to further enhance ABA responses remains unknown. Here, we show MYB96 interacts with the histone modifier HDA15 to suppress negative regulators of early ABA signaling. The MYB96-HDA15 complex co-binds to the promoters of a subset of RHO GTPASE OF PLANTS (ROP) genes, ROP6, ROP10, and ROP11, and represses their expression by removing acetyl groups of histone H3 and H4 from the cognate regions, particularly in the presence of ABA. In support, HDA15-deficient mutants display reduced ABA sensitivity and are susceptible to drought stress with derepression of the ROP genes, as observed in the myb96-1 mutant. Biochemical and genetic analyses show that MYB96 and HDA15 are interdependent in the regulation of ROP suppression. Thus, MYB96 confers maximal ABA sensitivity by regulating both positive and negative regulators of ABA signaling through distinctive molecular mechanisms.


Assuntos
Ácido Abscísico/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Histona Desacetilases/metabolismo , Fatores de Transcrição/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Catálise , Genótipo , Histona Desacetilases/genética , Histonas/metabolismo , Mutação , Plantas Geneticamente Modificadas/metabolismo , Regiões Promotoras Genéticas , Reprodutibilidade dos Testes , Transdução de Sinais , Fatores de Transcrição/genética
11.
Cytogenet Genome Res ; 157(3): 135-140, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30933954

RESUMO

We report a patient with developmental delay, brachydactyly type E, short stature, and tetralogy of Fallot. Brachydactyly-mental retardation syndrome (BDMR) was suspected based on the phenotype; however, array CGH excluded a 2q37 deletion, but identified a deletion encompassing the SHOX gene. BDMR is characterized by cognitive impairment, skeletal abnormalities involving hands and feet, short stature, and overweight. Most affected individuals carry relatively large 2q37 deletions encompassing HDAC4. This gene encodes a histone deacetylase involved in epigenetic regulation of cell growth and differentiation, specifically during endochondral bone formation in chondrocyte hypertrophy. Since SHOX haploinsufficiency can cause skeletal defects and short stature but would not fully explain the clinical picture of this patient, exome sequencing was performed, and a heterozygous HDAC8 frameshift mutation was identified. HDAC8 is a distinct histone deacetylase involved in cohesin recycling and is responsible for an X-linked dominant Cornelia de Lange-like phenotype. A new blended clinical phenotype may be explained by the result of a dual molecular diagnosis, which represents a combination of 2 independent genetic defects, with relevant implications for genetic counseling, clinical management, and prognosis.


Assuntos
Síndrome de Lange/diagnóstico , Mutação da Fase de Leitura , Deleção de Genes , Transtornos do Crescimento/diagnóstico , Histona Desacetilases/genética , Osteocondrodisplasias/diagnóstico , Proteínas Repressoras/genética , Proteína de Homoeobox de Baixa Estatura/genética , Criança , Hibridização Genômica Comparativa , Síndrome de Lange/genética , Feminino , Transtornos do Crescimento/genética , Haploinsuficiência , Humanos , Osteocondrodisplasias/genética , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
12.
Gynecol Oncol ; 154(1): 207-217, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30979588

RESUMO

OBJECTIVE: Though metastasis-associated protein 1 (MTA1) is widely overexpressed in human cancers and is associated with advanced clinicopathological characteristics and survival in related diseases, the association between MTA1 and endometrial cancer (EC) is little known and needs to be studied. METHODS: Western blot and immunohistochemistry were used to analyze protein expression level of cells and tissues, while real-time PCR was used for RNA detection. Bioinformatics tool analysis revealed the relationship between MTA1 and clinicopathological characteristics and survival. CCK-8 assay, colony-formation assay, cell scratch assay, and Transwell assay were performed to determine cell proliferation, migration and invasion abilities, respectively. RESULTS: The expression level of MTA1 was significantly higher in human EC tissues than in normal endometrium. MTA1 expression was correlated positively with lymph nodes metastasis and poor survival rate in EC. Experimentally overexpressed MTA1 could promote cell proliferation, migration and invasion abilities of EC cell lines Ishikawa, HEC-1B, and RL-952, while reduction of MTA1 inhibited these cell biological behaviors. Moreover, MTA1 could also reverse the negative effect of miR-30c, a direct modulator of MTA1, on EC cells. Our research also revealed that overexpression of MTA1 contributed to EC tumor growth, while knockdown of MTA1 resulted in tumor growth inhibition. Additionally, the phosphorylation levels of mTOR (S2448) and 4E-BP1 (T37/46) changed significantly along with AKT (T308) under regulation of MTA1, both in vivo and vitro. CONCLUSION: Our results showed that MTA1, as a downstream target of miR-30c, might promote EC progression via AKT/mTOR/4E-BP1 pathway, which indicated the potential therapy target of MTA1 in EC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias do Endométrio/metabolismo , Histona Desacetilases/metabolismo , MicroRNAs/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Repressoras/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Movimento Celular , Proliferação de Células , Progressão da Doença , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Xenoenxertos , Histona Desacetilases/biossíntese , Histona Desacetilases/genética , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Fosforilação , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Transdução de Sinais , Células Tumorais Cultivadas
13.
Mol Genet Genomic Med ; 7(5): e602, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30968599

RESUMO

BACKGROUND: Studying patients with rare Mendelian diabetes has uncovered molecular mechanisms regulating ß-cell pathophysiology. Previous studies have shown that Class IIa histone deacetylases (HDAC4, 5, 7, and 9) modulate mammalian pancreatic endocrine cell function and glucose homeostasis. METHODS: We performed exome sequencing in one adolescent nonautoimmune diabetic patient and detected one de novo predicted disease-causing HDAC4 variant (p.His227Arg). We screened our pediatric diabetes cohort with unknown etiology using Sanger sequencing. In mouse pancreatic ß-cell lines (Min6 and SJ cells), we performed insulin secretion assay and quantitative RT-PCR to measure the ß-cell function transfected with the detected HDAC4 variants and wild type. We carried out immunostaining and Western blot to investigate if the detected HDAC4 variants affect the cellular translocation and acetylation status of Forkhead box protein O1 (FoxO1) in the pancreatic ß-cells. RESULTS: We discovered three HDAC4 mutations (p.His227Arg, p.Asp234Asn, and p.Glu374Lys) in unrelated individuals who had nonautoimmune diabetes with various degrees of ß-cell loss. In mouse pancreatic ß-cell lines, we found that these three HDAC4 mutations decrease insulin secretion, down-regulate ß-cell-specific transcriptional factors, and cause nuclear exclusion of acetylated FoxO1. CONCLUSION: Mutations in HDAC4 disrupt the deacetylation of FoxO1, subsequently decrease the ß-cell function including insulin secretion, resulting in diabetes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Proteína Forkhead Box O1/metabolismo , Histona Desacetilases/genética , Células Secretoras de Insulina/metabolismo , Mutação de Sentido Incorreto , Proteínas Repressoras/genética , Acetilação , Transporte Ativo do Núcleo Celular , Adolescente , Animais , Núcleo Celular/metabolismo , Células Cultivadas , Feminino , Proteína Forkhead Box O1/genética , Humanos , Insulina/metabolismo , Masculino , Camundongos
14.
Mol Plant Microbe Interact ; 32(9): 1210-1228, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30986121

RESUMO

Histone deacetylases (HDACs) always function as corepressors and sometimes as coactivators in the regulation of fungal development and secondary metabolite production. However, the mechanism through which HDACs play positive roles in secondary metabolite production is still unknown. Here, classical HDAC enzymes were identified and analyzed in Aspergillus flavus, a fungus that produces one of the most carcinogenic secondary metabolites, aflatoxin B1 (AFB1). Characterization of the HDACs revealed that a class I family HDAC, HosA, played crucial roles in growth, reproduction, the oxidative stress response, AFB1 biosynthesis, and pathogenicity. To a lesser extent, a class II family HDAC, HdaA, was also involved in sclerotia formation and AFB1 biosynthesis. An in vitro analysis of HosA revealed that its HDAC activity was considerably diminished at nanomolar concentrations of trichostatin A. Notably, chromatin immunoprecipitation experiments indicated that HosA bound directly to AFB1 biosynthesis cluster genes to regulate their expression. Finally, we found that a transcriptional regulator, SinA, interacts with HosA to regulate fungal development and AFB1 biosynthesis. Overall, our results reveal a novel mechanism by which classical HDACs mediate the induction of secondary metabolite genes in fungi.


Assuntos
Aflatoxinas , Aspergillus flavus , Regulação Fúngica da Expressão Gênica , Histona Desacetilases , Aflatoxinas/biossíntese , Aflatoxinas/genética , Aspergillus flavus/enzimologia , Aspergillus flavus/genética , Aspergillus flavus/patogenicidade , Regulação Fúngica da Expressão Gênica/genética , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Ligação Proteica , Virulência/genética
15.
J Dairy Sci ; 102(6): 5706-5712, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954263

RESUMO

Antimicrobial peptides are a common defense against bacterial infections in many species and a significant part of the innate immune response of the bovine mammary gland. The objective of this study was to investigate the influence of epigenetic factors on vitamin D and toll-like receptor-mediated induction of ß-defensins in mammary epithelial cells. Primary bovine mammary epithelial cells were treated with lipopolysaccharide (LPS, 0 or 100 ng/mL), 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, 0 or 10 nM], and 5-aza-2'-deoxycytidine (5-Aza, inhibitor of DNA methyltransferase, 0 or 5 µM) or trichostatin A (TSA, inhibitor of histone deacetylase, 0 or 80 nM) in a factorial arrangement. Effects of treatments on ß-defensin gene expression along with genes for cytokines and enzymes known to be induced by LPS or 1,25(OH)2D3 were evaluated by quantitative PCR. The LPS treatment induced expression of ß-defensin (DEFB)3, DEFB5, DEFB7, DEFB10, enteric ß-defensin (EBD), lingual antimicrobial peptide (LAP), and tracheal antimicrobial peptide (TAP); whereas, the 1,25(OH)2D3 treatment increased DEFB5 and DEFB7 expression and decreased LAP. The 5-Aza treatment increased expression of DEFB3, DEFB5, DEFB10, EBD, LAP, and TAP in the presence and absence of LPS. The TSA treatment increased expression of DEFB3, DEFB4, DEFB5, DEFB7, and DEFB10 in the absence of LPS but decreased LPS-induced expression of and LAP and TAP. Together these results indicate that ß-defensin expression in bovine mammary epithelial cells is likely influenced by DNA methylation and histone acetylation. Investigation of environmental and nutritional factors that influence epigenetic control of ß-defensins in the mammary gland may be beneficial for improving resistance to intramammary infections.


Assuntos
Bovinos/metabolismo , Células Epiteliais/metabolismo , Histona Desacetilases/metabolismo , Lipopolissacarídeos/metabolismo , Glândulas Mamárias Animais/metabolismo , Metiltransferases/metabolismo , Vitamina D/análogos & derivados , beta-Defensinas/genética , Animais , Bovinos/genética , Metilação de DNA , Feminino , Histona Desacetilases/genética , Glândulas Mamárias Animais/citologia , Metiltransferases/genética , Vitamina D/metabolismo , beta-Defensinas/metabolismo
16.
Nat Commun ; 10(1): 1589, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30962442

RESUMO

Transmembrane and coiled-coil domains 1 (TMCO1) is a recently identified Ca2+ leak channel in the endoplasmic reticulum. TMCO1 dysfunction in humans is associated with dysmorphism, mental retardation, glaucoma and the occurrence of cancer. Here we show an essential role of TMCO1 in osteogenesis mediated by local Ca2+/CaMKII signaling in osteoblasts. TMCO1 levels were significantly decreased in bone from both osteoporosis patients and bone-loss mouse models. Tmco1-/- mice exhibited loss of bone mass and altered microarchitecture characteristic of osteoporosis. In the absence of TMCO1, decreased HDAC4 phosphorylation resulted in nuclear enrichment of HADC4, which leads to deacetylation and degradation of RUNX2, the master regulator of osteogenesis. We further demonstrate that TMCO1-mediated Ca2+ leak provides local Ca2+ signals to activate the CaMKII-HDAC4-RUNX2 signaling axis. The establishment of TMCO1 as a pivotal player in osteogenesis uncovers a novel potential therapeutic target for ameliorating osteoporosis.


Assuntos
Canais de Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteínas de Membrana/metabolismo , Osteoblastos/metabolismo , Osteoporose/fisiopatologia , Idoso , Animais , Canais de Cálcio/genética , Sinalização do Cálcio , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Feminino , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Pessoa de Meia-Idade , Osteogênese/fisiologia , Osteoporose/metabolismo , Ovariectomia , Estabilidade Proteica , Transdução de Sinais
17.
Life Sci ; 223: 1-8, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30862568

RESUMO

AIMS: The aim of this study was to investigate the relationship between anti-HBV treatment and the regulation of HDACs during HBV DNA replication. METHODS: HDAC activities and HBV DNA levels in CHB patients' sera were measured and correlation analysis was made. The changes of HDAC2, HDAC6, AH3 and histone H3 levels in normal control and 4 CHB patient liver tissue samples before and after antiviral treatment were examined. The HDAC inhibitor, TSA, anti-HBV agents, ETV and IFN-α were used to stimulate HepG2.2.15 cells. The levels of HBV DNA, pgRNA in supernatants, and cccDNA in the cells were determined by PCR. The HDAC activity, HDAC6, HDAC2, AH3 and H3 protein levels in cells were tested at days 3, 6, and 9 after treatments. KEY FINDINGS: HDAC activity was positively correlated with HBV DNA in the HBV patients' sera. The levels of HDAC2, HDAC6 and AH3 were notably decreased after antiviral treatment. When compared with antiviral treatment group, the normal liver tissue showed obviously decreased HDAC2, HDAC6 and AH3 protein levels. In vitro study, the level of HBV DNA, the HDAC activity, and the HDAC2, HDAC6 and AH3 protein levels decreased in the ETV, IFN-α and TSA groups compared with the control group. The pgRNA level in supernatants was declined in the IFN-α group and increased in the ETV and TSA groups. cccDNA expression was suppressed by IFN-α. SIGNIFICANCE: The changes of HBV replicative products during antiviral treatment are associated with histone deacetylation. Acetylated histone H3 is involved in the process of hepatitis B virus DNA replication.


Assuntos
Replicação do DNA/efeitos dos fármacos , DNA Viral/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Histona Desacetilases/metabolismo , Histonas/genética , Adulto , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Técnicas de Cultura de Células , Replicação do DNA/genética , Feminino , Células Hep G2 , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/enzimologia , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/genética , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
18.
Int J Mol Sci ; 20(6)2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30884785

RESUMO

Fibrosis is characterized by excessive deposition of the extracellular matrix and develops because of fibroblast differentiation during the process of inflammation. Various cytokines stimulate resident fibroblasts, which differentiate into myofibroblasts. Myofibroblasts actively synthesize an excessive amount of extracellular matrix, which indicates pathologic fibrosis. Although initial fibrosis is a physiologic response, the accumulated fibrous material causes failure of normal organ function. Cardiac fibrosis interferes with proper diastole, whereas pulmonary fibrosis results in chronic hypoxia; liver cirrhosis induces portal hypertension, and overgrowth of fibroblasts in the conjunctiva is a major cause of glaucoma surgical failure. Recently, several reports have clearly demonstrated the functional relevance of certain types of histone deacetylases (HDACs) in various kinds of fibrosis and the successful alleviation of the condition in animal models using HDAC inhibitors. In this review, we discuss the therapeutic potential of HDAC inhibitors in fibrosis-associated human diseases using results obtained from animal models.


Assuntos
Fibrose/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Inflamação/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Matriz Extracelular/genética , Matriz Extracelular/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose/genética , Histona Desacetilases/genética , Humanos , Hipertensão Portal/tratamento farmacológico , Hipertensão Portal/genética , Hipertensão Portal/patologia , Inflamação/genética , Inflamação/patologia , Modelos Animais , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/patologia
19.
Plant Physiol Biochem ; 139: 207-214, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30908972

RESUMO

ABSCISIC ACID-INSENSITIVE 3 (ABI3) is one of the essential transcription factors of ABSCISIC ACID (ABA) signaling, functioning in seed germination, early seedling development, and abiotic stress tolerance. A recent study showed that epigenetic repression of ABI3 by brassinosteroid (BR)-activated BRI1 EMS SUPPRESSOR1 (BES1)-TOPLESS (TPL)HISTONE DEACETYLASE 19 (HDA19) repressor complex is a critical event for promoting seed germination and early seedling development. However, other physiological roles of the repression of ABI3 and ABA responses by BES1-mediated BR signaling pathways remain elusive. Here, we show that BES1-mediated suppression of ABI3 promotes floral transition and ABI3 acts as a negative regulator for flowering. Ectopic expression of ABI3 specifically compromised the early flowering phenotype of bes1-D and induced severe late-flowering phenotypes in wild-type Arabidopsis and Solanum lycopersicum plants. Both spatiotemporal expression patterns and global transcriptome analysis of ABI3-overexpressing plants supported the biological roles of ABI3 in the negative regulation of floral transition and reproduction. Finally, we confirmed that the loss of function of ABI3 induced early-flowering phenotypes in both long- and short-day conditions. In conclusion, our data suggest that BES1-mediated regulation of ABI3 is important in the reproductive phase transition of plants.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Brassinosteroides/metabolismo , Flores/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Fatores de Transcrição/metabolismo , Proteínas de Arabidopsis/genética , Flores/genética , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Fatores de Transcrição/genética
20.
Biomed Pharmacother ; 111: 976-982, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841477

RESUMO

Lysine crotonylation is a new posttranslational modification (PTM) type identified on histones, which is enriched on active gene promoters or potential enhancers in mammalian cell genomes. However, the function of lysine crotonylation in the cancer process is not known. Intriguingly, we found that lysine crotonylation expression is down-regulated in liver, stomach, kidney carcinomas, and up-regulated in thyroid, esophagus, colon, pancreas and lung carcinomas. In hepatocellular carcinoma (HCC), lysine crotonylation expression is correlated with Tumour, Node, and Metastasis (TNM) stage. Besides, the crotonylation level is increased by knocking down HDACs or adding HDACs inhibitor, TSA, and thus inhibits hepatoma cell motility and proliferation. Taken together, our findings opened up a new field for the investigation and understanding of the biological role of lysine crotonylation.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Lisina/genética , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
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