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1.
APMIS ; 128(1): 3-9, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31628675

RESUMO

Biliary tract cancers (BTC) are a rare heterogeneous disease group with a dismal prognosis and limited treatment options. The mutational landscape consists of genetic aberrations both shared by and characteristic for anatomical location. Here, we present exome sequencing data on 22 genes from a phase 2 trial using a clinically validated panel used in patients with colorectal cancer. A total of 56 patients were included in a one-armed phase 2 trial investigating the treatment combination of capecitabine, gemcitabine, oxaliplatin, and cetuximab. Tissue DNA yield and quality allowed analysis of 30 patients on our panel including 22 genes. ARID1A (33%) and TP53 (33%) were found to be most frequently mutated followed by KRAS mutations found in 20% of the patients. Mutational aberrations in ARID1A were found more prevalent than expected, whereas TP53 and KRAS were in concordance with earlier reported data. Mutation in CTNNB1 was significantly associated with poor prognosis. Our panel is clinically validated and suitable for a high volume of samples to detect mutations in patients with BTC. However, it is reasonable to assume that the clinical utility could be optimized in this patient group by extending the panel to include BTC specific mutations with potential therapeutic consequences such as IDH1/2, FGFR fusions, ERBB3, and BRCA1/2.


Assuntos
Neoplasias dos Ductos Biliares/genética , Exoma , Mutação , Adulto , Idoso , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Inclusão em Parafina , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Análise de Sequência de DNA , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , beta Catenina/genética
2.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(5): 609-614, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31699190

RESUMO

Objective To detect the methylation status of SALL3 gene promoter region in normal cervical tissues,cervical cancer tissues,and cervical cancer cell lines and thus explore the relationship between methylation status and the expression of SALL3 gene.Methods The DNA methylation statuses of SALL3 gene in normal cervical,cervical cancer tissues and cervical cancer cell lines were analyzed by methylation-specific PCR(MS-PCR).The expressions of SALL3 mRNA in cervical cancer cell lines,cervical cancer tissues,and normal cervical tissues were detected by RT-PCR.Results In cervical cancer and matched peri-carcinomatous samples,the methylation levels of SALL3 were up-regulated(CCa vs.CCap:P=0.046;CCa vs.NC P=0.039)and the protein expressions were down-regulated(CCa vs.CCap:P=0.012;CCa vs.NC P=0.000)when compared with normal cervix samples.The mRNA levels of SALL3 in HeLa and SiHa cells treated with 5-Azacytidine were elevated in a dose-dependent manner(HeLa:P=0.001;SiHa:P=0.002).The methylation level of SALL3 was higher in high risk human papillomavirus(HPV)-positive cervical samples than in HPV-negative cervical samples(P=0.014),which also resulted in a descending SALL3 expression in HPV-positive samples(P=0.021).Conclusions The hypermethylation of SALL3 in promoter regions inhibits the expression of SALL3 in cervical cancer tissue samples.Infection with high-risk HPV serotypes may increase the methylation of SALL3 promoter region,silence its expression,and thus promote the development of cervical cancer.


Assuntos
Metilação de DNA , Proteínas de Homeodomínio/genética , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Neoplasias do Colo do Útero/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Infecções por Papillomavirus/genética , RNA Mensageiro/genética
3.
Exp Suppl ; 111: 263-298, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588536

RESUMO

Congenital pituitary hormone deficiency is a disabling condition. It is part of a spectrum of disorders including craniofacial midline developmental defects ranging from holoprosencephaly through septo-optic dysplasia to combined and isolated pituitary hormone deficiency. The first genes discovered in the human disease were based on mouse models of dwarfism due to mutations in transcription factor genes. High-throughput DNA sequencing technologies enabled clinicians and researchers to find novel genetic causes of hypopituitarism for the more than three quarters of patients without a known genetic diagnosis to date. Transcription factor (TF) genes are at the forefront of the functional analysis of novel variants of unknown significance due to the relative ease in in vitro testing in a research lab. Genetic testing in hypopituitarism is of high importance to the individual and their family to predict phenotype composition, disease progression and to avoid life-threatening complications such as secondary adrenal insufficiency.This chapter aims to highlight our current understanding about (1) the contribution of TF genes to pituitary development (2) the diversity of inheritance and phenotype features in combined and select isolated pituitary hormone deficiency and (3) provide an initial assessment on how to approach variants of unknown significance in human hypopituitarism. Our better understanding on how transcription factor gene variants lead to hypopituitarism is a meaningful step to plan advanced therapies to specific genetic changes in the future.


Assuntos
Hipopituitarismo/genética , Hipófise/fisiopatologia , Fatores de Transcrição/genética , Animais , Holoprosencefalia , Humanos , Camundongos , Mutação
4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1627-1632, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607324

RESUMO

OBJECTIVE: To study the regulatory effect of deubiquitinase MYSM1 on differentiation of B cells to plasma cells. METHODS: The interfering and overexpression plasmids of MYSM1 were constructed and then the corresponding lentiviruses were packaged. Human CD19+ B cells were isolated from human peripheral blood with Miltenyi B cell isolation kit. Purified CD19+ B cells were transduced with lentiviruses and then treated with LPS, the CD138 expression was detected by flow cytometry. The expression of transcription factor was determined by quantitative PCR. RESULTS: The differentiation of B cells to plasma cells was enhanced after interfering in MYSM1 expression. Quantitative PCR showed that mRNA levels of Pax5 and Bach2 in cells with interfering in MYSM1 were much lower than their counterpart (P<0.01), and mRNA levels of Prdm1 and Xbp1 in cells with interfering in MYSM1 were much higher than their counterpart (P<0.01). On the contrary, the differentiation of B cells to plasma cells was inhibited after the overexpression of MYSM1. Quantitative PCR showed that mRNA levels of Pax5 and Bach2 in cells with MYSM1 overexpression were higher than those in control cells (P<0.01), and mRNA levels of Prdm1 and Xbp1 in cells with MYSM1 overexpression were much lower than those in their counterpart (P<0.01). CONCLUSION: MYSM1 negatively regulates differentiation of human B cells to plasma cells.


Assuntos
Linfócitos B , Proteínas de Ligação a DNA/genética , Plasmócitos , Fatores de Transcrição/genética , Diferenciação Celular , Enzimas Desubiquitinantes , Humanos
5.
DNA Cell Biol ; 38(11): 1346-1356, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31618054

RESUMO

DNA hydroxymethylation is one of the major epigenetic mechanisms mediating the development of several human cancers. This study aimed to identify key hydroxymethylated genes and transcription factors (TFs) associated with alpha-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC) using whole-genome DNA hydroxymethylation profiling. A total of 615 differentially hydroxymethylated regions (DHMRs) were identified from AFP-negative HCC tissues compared to adjacent normal tissues. DHMR-associated genes were significantly enriched in gene ontology functions associated with actin binding, cell leading edge, and blood vessel morphogenesis and pathways such as MAPK signaling pathway, neuroactive ligand-receptor interaction, and axon guidance. Moreover, protein-protein interaction (PPI) network analysis showed that PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2 (SMARCA2) had higher degrees and were hub nodes. Furthermore, TF prediction analysis showed that TFs, such as nuclear factor I C (NFIC) and GATA binding protein 3 (GATA3), regulated many DHMR-associated genes. Our findings reveal that key hydroxymethylated genes such as PHLPP1 and SMARCA2, as well as TFs such as NFIC and GATA, may be involved in the development of AFP-negative HCC. These molecules may be potential biomarkers for AFP-negative HCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Metilação de DNA , Neoplasias Hepáticas/genética , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/metabolismo , Estudos de Casos e Controles , Epigênese Genética/fisiologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , alfa-Fetoproteínas/metabolismo
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 993-995, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598943

RESUMO

OBJECTIVE: To explore the genetic etiology of a pedigree affected with tricho-rhino-phalangeal syndrome. METHODS: Next-generation sequencing (NGS) using a gene panel for hereditary osteopathies was carried out for the proband. Suspected mutation was validated in the proband and her parents by Sanger sequencing. RESULTS: A heterozygous frameshift variation c.1995dupA (p.Gly666Argfs*20) of the TRPS1 gene was detected in the proband but not in her parents. CONCLUSION: The novel c.1995dupA (p.Gly666Argfs*20) mutation of the TRPS1 gene probably underlies the disease in the proband.


Assuntos
Proteínas de Ligação a DNA/genética , Dedos/anormalidades , Mutação da Fase de Leitura , Doenças do Cabelo/genética , Síndrome de Langer-Giedion/genética , Nariz/anormalidades , Fatores de Transcrição/genética , Feminino , Humanos , Linhagem
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 1028-1030, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598953

RESUMO

OBJECTIVE: To carry out genetic testing for a family with two pregnancies affected with hydrops fetalis and dilated cardiomyopathy (DCM) of the fetus. METHODS: DNA was extracted from fetal tissue as well as peripheral blood samples from the couple. Single nucleotide polymorphism array (SNP array) and next-generation sequencing (NGS) were carried out to screen potential mutation. Suspected mutation was validated with PCR and Sanger sequencing. RESULTS: The manifestation of fetal echocardiography was consistent with DCM. No obvious abnormality was found by SNP array analysis. A hemizygous c.481G>A (p.G161R) mutation of the TAZ gene was detected in the male fetus by NGS and confirmed by Sanger sequencing. The mutation was inherited from his mother. CONCLUSION: Barth syndrome due to the c.481G>A mutation of the TAZ gene probably underlies the recurrent hydrops fetalis and fetal DCM in this family.


Assuntos
Cardiomiopatia Dilatada/genética , Hidropisia Fetal/genética , Fatores de Transcrição/genética , Síndrome de Barth/genética , Ecocardiografia , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Gravidez
8.
DNA Cell Biol ; 38(11): 1374-1386, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31599655

RESUMO

This study was conducted using TagSNPs to systematically explore the relationship between ARID5B polymorphisms and the occurrence, clinical characterization, and prognosis of acute myeloid leukemia (AML). A total of 569 unrelated AML patients and 410 healthy individuals from West China were recruited, and ARID5B TagSNPs were genotyped using iMLDR® (improved multiplex ligation detection reaction). It was found that the association of ARID5B polymorphisms with AML was most significant in acute promyelocytic leukemia (APL), and exclusively in males, the mutant alleles of rs6415872, rs2393726, rs7073837, rs10821936, and rs7089424 were found to increase the risk of developing APL in men, the odds ratio (OR) were 1.36, 1.74, 1.45, 1.53, and 1.56 (all p < 0.05), respectively. Haplotype analysis revealed that haplotype [AACCG] increased the risk of male APL with an OR of 1.53 (95% confidence interval: 1.10-2.14, p = 0.012). Besides, there was a strong positive additive interaction between rs6415872 and rs10821936, rs7089424, respectively, and cases attributed to the interaction of rs6415872, rs10821936, and rs7089424 accounted for 100%. Furthermore, ARID5B single nucleotide polymorphisms were found associated with clinical features of AML, and rs6415872 was shown to be an independent prognosis factor in APL patients. Besides, dual luciferase report assay showed that rs6415872 may affect the binding activity of PPARG with ARID5B. ARID5B polymorphisms contribute to male APL risk, clinical feature, and prognosis, suggesting the importance of ARDI5B in AML pathogenesis and development, and the gender and subtype preference may prompt some specific mechanisms of ARID5B. Besides, ARID5B polymorphisms might be a potential prognosis biomarker.


Assuntos
Proteínas de Ligação a DNA/genética , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Células HEK293 , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/epidemiologia , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Prognóstico , Caracteres Sexuais , Análise de Sobrevida
9.
Cytogenet Genome Res ; 159(1): 1-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31658463

RESUMO

The switch/sucrose non-fermenting (SWI/SNF) complex is an ATP-dependent chromatin remodeller that regulates the spacing of nucleosomes and thereby controls gene expression. Heterozygous mutations in genes encoding subunits of the SWI/SNF complex have been reported in individuals with Coffin-Siris syndrome (CSS), with the majority of the mutations in ARID1B. CSS is a rare congenital disorder characterized by facial dysmorphisms, digital anomalies, and variable intellectual disability. We hypothesized that mutations in genes encoding subunits of the ubiquitously expressed SWI/SNF complex may lead to alterations of the nucleosome profiles in different cell types. We performed the first study on CSS-patient samples and investigated the nucleosome landscapes of cell-free DNA (cfDNA) isolated from blood plasma by whole-genome sequencing. In addition, we studied the nucleosome landscapes of CD14+ monocytes from CSS-affected individuals by nucleosome occupancy and methylome-sequencing (NOMe-seq) as well as their expression profiles. In cfDNA of CSS-affected individuals with heterozygous ARID1B mutations, we did not observe major changes in the nucleosome profile around transcription start sites. In CD14+ monocytes, we found few genomic regions with different nucleosome occupancy when compared to controls. RNA-seq analysis of CD14+ monocytes of these individuals detected only few differentially expressed genes, which were not in proximity to any of the identified differential nucleosome-depleted regions. In conclusion, we show that heterozygous mutations in the human SWI/SNF subunit ARID1B do not have a major impact on the nucleosome landscape or gene expression in blood cells. This might be due to functional redundancy, cell-type specificity, or alternative functions of ARID1B.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Proteínas Nucleares/genética , Nucleossomos/genética , Fatores de Transcrição/genética , Adolescente , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Criança , Pré-Escolar , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Monócitos/citologia , Adulto Jovem
10.
Zhonghua Bing Li Xue Za Zhi ; 48(10): 791-795, 2019 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-31594044

RESUMO

Objective: To correlate chromosomal translocations of DUSP22 or TP63 with clinical significance in ALK-negative anaplastic large cell lymphoma (ALK(-)ALCL). Methods: Thirty-two patients with ALK(-)ALCL were selected from January 2004 to January 2014 at Fujian Provincial Hospital for the detection of chromosomal translocations of DUSP22 and TP63 by fluorescence in situ hybridization (FISH). The relationship between DUSP22 and TP63 chromosomal translocations and the clinicopathological parameters of ALK(-)ALCL was analyzed. Results: Among the 32 ALK(-)ALCL patients, 7(21.8%) had DUSP22 gene rearrangement (DUSP22(+)ALK(-)ALCL). Three patients (9.4%) had TP63 gene rearrangement (TP63(+) ALK(-)ALCL). There were 22 patients (68.8%) without rearrangement of either DUSP22 or TP63 (DUSP22(-)TP63(-)ALK(-)ALCL). The patients with DUSP22(+) ALK(-)ALCL were among the younger, and the patients with TP63(+) ALK(-)ALCL were among the elder. The mean age of patients with DUSP22(-)TP63(-)ALK(-) ALCL was between those of DUSP22(+)ALK(-)ALCL and TP63(+) ALK(-)ALCL (P<0.05). Based on Ann Arbor staging, incidence of DUSP22 gene rearrangement decreased as the clinical stage of ALK(-)ALCL increased (P<0.05). Incidence of TP63 gene rearrangement cases increases in patients at more advanced clinical stage(P<0.05). The five-year survival rate and prognosis of patients with DUSP22(+)ALK(-)ALCL were the highest. Patients with TP63(+) ALK(-)ALCL had the lower five-year survival and the worse prognosis (P<0.05). Conclusion: Presences of DUSP22 and TP63 chromosomal translocations correlate with the clinical stages and prognosis of ALK(-)ALCL and may be used for the differential diagnosis, determination of tumor aggressiveness and prognostication of ALK(-)ALCL.


Assuntos
Quinase do Linfoma Anaplásico/genética , Fosfatases de Especificidade Dupla/genética , Linfoma Anaplásico de Células Grandes/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Fatores de Transcrição/genética , Translocação Genética , Proteínas Supressoras de Tumor/genética , Humanos , Hibridização in Situ Fluorescente
11.
DNA Cell Biol ; 38(11): 1278-1291, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31584843

RESUMO

The plants being sessile cannot escape from the adverse environmental stresses, hence get negatively affected in terms of their growth and yield. Transcriptional control simultaneously regulate different cellular processes, minimizing the deleterious effects of these stresses. The salicylic acid (SA)-inducible WRKY family of transcription factors auto or crossregulate the stress signaling in response to abiotic and biotic stresses, facilitating enhanced stress tolerance. In this study, we characterized the group III WRKY gene, JcWRKY2 from ecological and economical valued shrub Jatropha curcas. The JcWRKY2 tobacco transgenics showed improved physiological growth parameters, elevated chlorophyll content, improved antioxidative activities, and increased endogenous SA with both salt and SA stress. Interestingly, the pretreatment with SA and hydrogen peroxide facilitated improved germination of transgenic seeds with salinity stress. The transgenics showed differential regulation of antioxidative enzymes, calcium/calmodulin, dehydrins, and phospholipase genes with salt and SA stress. The increased SA content in transgenics on stress treatments, enhanced the antioxidant capacity leading to reduced susceptibility to stresses. Thus, JcWRKY2 transgenics participate in SA-mediated, improved antioxidative status during salinity stress with reduced reactive oxygen species damage.


Assuntos
Jatropha/genética , Estresse Salino/genética , Tolerância ao Sal/genética , Tabaco/genética , Fatores de Transcrição/fisiologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Germinação/efeitos dos fármacos , Germinação/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Plantas Geneticamente Modificadas , Salinidade , Cloreto de Sódio/farmacologia , Estresse Fisiológico/genética , Tabaco/efeitos dos fármacos , Tabaco/crescimento & desenvolvimento , Fatores de Transcrição/genética
12.
Nat Med ; 25(9): 1428-1441, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501614

RESUMO

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.


Assuntos
Imunidade Celular , Neoplasias/imunologia , Estresse Psicológico/imunologia , Fatores de Transcrição/genética , Animais , Ansiedade/sangue , Ansiedade/induzido quimicamente , Ansiedade/imunologia , Ansiedade/psicologia , Comportamento Animal/fisiologia , Carcinógenos/toxicidade , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/psicologia , Corticosterona/sangue , Células Dendríticas/transplante , Regulação Neoplásica da Expressão Gênica , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/psicologia , Ativação Linfocitária/genética , Camundongos , Monitorização Imunológica/métodos , Neoplasias/induzido quimicamente , Neoplasias/genética , Neoplasias/psicologia , Receptores de Glucocorticoides/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/psicologia , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/genética , Estresse Psicológico/terapia , Fatores de Transcrição/imunologia
13.
Nucleic Acids Res ; 47(18): 9934-9949, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31504787

RESUMO

The pathogenicity of Mycobacterium tuberculosis depends upon its ability to catabolize host cholesterol. Upregulation of the methylcitrate cycle (MCC) is required to assimilate and detoxify propionyl-CoA, a cholesterol degradation product. The transcription of key genes prpC and prpD in MCC is activated by MtPrpR, a member of a family of prokaryotic transcription factors whose structures and modes of action have not been clearly defined. We show that MtPrpR has a novel overall structure and directly binds to CoA or short-chain acyl-CoA derivatives to form a homotetramer that covers the binding cavity and locks CoA tightly inside the protein. The regulation of this process involves a [4Fe4S] cluster located close to the CoA-binding cavity on a neighboring chain. Mutations in the [4Fe4S] cluster binding residues rendered MtPrpR incapable of regulating MCC gene transcription. The structure of MtPrpR without the [4Fe4S] cluster-binding region shows a conformational change that prohibits CoA binding. The stability of this cluster means it is unlikely a redox sensor but may function by sensing ambient iron levels. These results provide mechanistic insights into this family of critical transcription factors who share similar structures and regulate gene transcription using a combination of acyl-CoAs and [4Fe4S] cluster.


Assuntos
Acil Coenzima A/química , Proteínas de Bactérias/química , Mycobacterium tuberculosis/genética , Fatores de Transcrição/química , Acil Coenzima A/genética , Proteínas de Bactérias/genética , Colesterol/genética , Regulação Bacteriana da Expressão Gênica/genética , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/patogenicidade , Proteínas PrPC/química , Proteínas PrPC/genética , Fatores de Transcrição/genética , Tuberculose/genética , Tuberculose/microbiologia
14.
J Agric Food Chem ; 67(37): 10513-10520, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31475823

RESUMO

Amino acids can stimulate milk fat synthesis, but the underlying molecular mechanism is still largely unknown. In this study, we studied the regulatory role and corresponding molecular mechanism of cAMP response element-binding protein-regulated transcription coactivator 2 (CRTC2) in amino acid-induced milk fat synthesis in mammary epithelial cells. We showed that leucine and methionine stimulated CRTC2 but not p-CRTC2(Ser171) expression and nuclear localization in cow mammary epithelial cells. Knockdown of CRTC2 decreased milk fat synthesis and sterol regulatory element binding protein 1c (SREBP-1c) expression and activation, whereas its overexpression had the opposite effects. Neither knockdown nor overexpression of CRTC2 affected ß-casein synthesis and phosphorylation of the machanistic target of rapamycin (mTOR), suggesting that CRTC2 only regulates milk fat synthesis. CRTC2 knockdown abolished the stimulation of leucine and methionine on SREBP-1c expression and activation. Knockdown or overexpression of CRTC2 did not affect the protein level of cAMP-response element-binding protein (CREB) and its phosphorylation but decreased or increased the binding of p-CREB to the promoter of SREBP-1c gene and its mRNA expression, respectively. Mutation of Ser171 of CRTC2 did not alter the stimulation of CRTC2 on SREBP-1c expression and activation, further suggesting that CRTC2 functions in the nucleus. mTOR inhibition by rapamycin totally blocked the stimulation of leucine and methionine on CRTC2 expression. The expression of CRTC2 was dramatically higher in the mouse mammary gland of lactation period, compared with that of the dry and puberty periods, whereas p-CRTC2(Ser171) was not changed, further supporting that CRTC2 is a key transcription coactivator for milk fat synthesis. These results uncover that CRTC2 is a key transcription coactivator of amino acid-stimulated mTOR-mediated milk fat synthesis in mammary epithelial cells.


Assuntos
Aminoácidos/metabolismo , Bovinos/metabolismo , Células Epiteliais/metabolismo , Gorduras/metabolismo , Glândulas Mamárias Animais/citologia , Leite/metabolismo , Fatores de Transcrição/metabolismo , Animais , Bovinos/genética , Feminino , Glândulas Mamárias Animais/metabolismo , Camundongos , Fosforilação , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética
15.
BMC Med Genet ; 20(1): 149, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477042

RESUMO

BACKGROUND: Rotator cuff disease is a widespread musculoskeletal pathology and a major cause of shoulder pain. Studies on familial predisposition suggest that genetic plays a role in the pathogenesis of rotator cuff disease. Several genes are responsible for rotator cuff disease. The aim of this study was to perform a systematic review on genetic association between rotator cuff disease and genes variations. METHODS: A systematic review of the literature was performed, in accordance with the PRISMA guidelines. PubMed, Medline, CINAHL, Cochrane, Embase and Google Scholar databases were searched comprehensively using the keywords: "Rotator cuff", "Gene", "Genetic", "Predisposition", "Single-nucleotide polymorphism" and "Genome-wide association". RESULTS: 8 studies investigating genes variations associated with rotator cuff tears were included in this review. 6 studies were case-control studies on candidate genes and 2 studies were GWASs. A significant association between SNPs and rotator cuff disease was found for DEFB1, FGFR1, FGFR3, ESRRB, FGF10, MMP-1, TNC, FCRL3, SASH1, SAP30BP, rs71404070 located next to cadherin8. Contradictory results were reported for MMP-3. CONCLUSION: Further investigations are warranted to identify complete genetic profiles of rotator cuff disease and to clarify the complex interaction between genes, encoded proteins and environment. This may lead to individualized strategies for prevention and treatment of rotator cuff disease. LEVEL OF EVIDENCE: Level IV, Systematic Review.


Assuntos
Variação Genética , Estudo de Associação Genômica Ampla , Lesões do Manguito Rotador/genética , Caderinas/genética , Bases de Dados Factuais , Fator 10 de Crescimento de Fibroblastos/genética , Humanos , Metaloproteinase 1 da Matriz/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptores Estrogênicos/genética , Receptores Imunológicos/genética , Manguito Rotador , Tenascina/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , beta-Defensinas/genética
16.
Int Heart J ; 60(5): 1113-1122, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31484864

RESUMO

Occurring in about 1% of all live births, congenital heart defects (CHDs) represent the most frequent type of developmental abnormality and account for remarkably increased infant morbidity and mortality. Aggregating studies demonstrate that genetic components have a key role in the occurrence of CHDs. Nevertheless, due to pronounced genetic heterogeneity, the genetic causes of CHDs remain unclear in most patients. In this research, 114 unrelated patients affected with CHDs and 218 unrelated individuals without CHDs served as controls were recruited. The coding regions and splicing donors/acceptors of the ISL1 gene, which codes for a transcription factor required for proper cardiovascular development, were screened for mutations by sequencing in all study participants. The functional characteristics of an identified ISL1 mutation were delineated with a dual-luciferase reporter assay system. As a result, a new heterozygous ISL1 mutation, NM_002202.2: c.225C>G; p. (Tyr75*), was discovered in an index patient with double outlet right ventricle and ventricular septal defect. Analysis of the proband's family unveiled that the mutation co-segregated with the CHD phenotype. The nonsense mutation was absent in the 436 control chromosomes. Biological analysis showed that the mutant ISL1 protein had no transcriptional activity. Furthermore, the mutation nullified the synergistic activation between ISL1 and TBX20, another CHD-associated transcription factor. This research for the first time links an ISL1 loss-of-function mutation to double outlet right ventricle in humans, which adds insight to the molecular pathogenesis underpinning CHDs, suggesting potential implications for timely personalized management of CHD patients.


Assuntos
Dupla Via de Saída do Ventrículo Direito/genética , Genes Reporter/genética , Predisposição Genética para Doença/epidemiologia , Proteínas com Homeodomínio LIM/genética , Mutação com Perda de Função/genética , Fatores de Transcrição/genética , Estudos de Casos e Controles , Causalidade , Pré-Escolar , China/epidemiologia , Dupla Via de Saída do Ventrículo Direito/diagnóstico por imagem , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Heterozigoto , Hospitais Universitários , Humanos , Incidência , Lactente , Masculino , Mutação , Linhagem , Prognóstico , Estudos Retrospectivos , Medição de Risco
17.
Acta Virol ; 63(3): 286-291, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507194

RESUMO

Schmallenberg virus (SBV), a neurotropic member of the genus Orthobunyavirus, infects ruminants and causes neurological lesions and fetal malformations including cerebellar hypoplasia, hydranencephaly, and porencephaly. The aim of this study is to establish intracerebral (i.c.) infection of SBV in newborn BALB/c mice and to investigate some of the transcription factors in brain. For this aim, brain samples of newborn BALB/c mice which were infected with SBV i.c. were analyzed by plaque titration and real-time RT-PCR for T-bet, Gata3, RoRγt, Foxp3 and Eomes mRNA levels. Study results showed that SBV can replicate in BALB/c mice brain and cause death of newborn mice with generation of infectious viral particles. Analyses of transcription factor mRNA levels indicated up-regulation of T-bet, Gata3, RoRγt, Foxp3 and down-regulation of Eomes. In this report, we introduce preliminary data of T cell transcription factors affected by SBV infection of BALB/c mice. Keywords: Eomes; Foxp3; Gata3; RoRγt; Schmallenberg virus; T-bet.


Assuntos
Encéfalo , Infecções por Bunyaviridae , Regulação da Expressão Gênica , Orthobunyavirus , Fatores de Transcrição , Animais , Animais Recém-Nascidos , Encéfalo/virologia , Infecções por Bunyaviridae/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ruminantes , Fatores de Transcrição/genética , Replicação Viral
18.
J Agric Food Chem ; 67(42): 11815-11824, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31550160

RESUMO

Yan73 is a teinturier Vitis vinifera variety with red berry flesh, but the molecular mechanisms underlying its flesh coloration remain unclear. We analyzed the flavonoid metabolic and transcriptome profiles of Yan73 berry red and white flesh using HPLC-ESI-MS/MS and RNA-sequencing technologies. Anthocyanins are the main flavonoids responsible for Yan73 berry flesh color, and the coloration is coordinately regulated by the VvMYBA1 transcriptional activator and VvMYBC2-L1 transcriptional repressor. Furthermore, yeast one- and two-hybrid, dual luciferase, and bimolecular fluorescence complementation assays suggested that VvMYBA1 positively regulates Yan73 berry flesh color via interactions with VvWDR1 and the activation of the VvCHI3, VvOMT, and VvGST4 promoters, whereas VvMYBC2-L1 negatively regulates Yan73 berry flesh color, possibly by competing with the R2R3-MYB transcriptional activators for bHLH partners or by repressing VvOMT and VvGST4 expression. Our findings provide new insights into the molecular mechanisms regulating grape flesh color.


Assuntos
Frutas/química , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas Repressoras/genética , Vitis/genética , Cor , Frutas/genética , Frutas/metabolismo , Proteínas de Plantas/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Vitis/química , Vitis/metabolismo
19.
Nat Cell Biol ; 21(10): 1191-1205, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31548610

RESUMO

Cells of multicellular organisms need to adopt specific morphologies. However, the molecular mechanisms bringing about membrane topology changes are far from understood-mainly because knowledge of membrane-shaping proteins that can promote local membrane curvatures is still limited. Our analyses unveiled that several members of a large, previously unrecognised protein family, which we termed N-Ank proteins, use a combination of their ankyrin repeat array and an amino (N)-terminal amphipathic helix to bind and shape membranes. Consistently, functional analyses revealed that the N-Ank protein ankycorbin (NORPEG/RAI14), which was exemplarily characterised further, plays an important, ankyrin repeat-based and N-terminal amphipathic helix-dependent role in early morphogenesis of neurons. This function furthermore required coiled coil-mediated self-assembly and manifested as ankycorbin nanodomains marked by protrusive membrane topologies. In summary, here, we unveil a class of powerful membrane shapers and thereby assign mechanistic and cell biological functions to the N-Ank protein superfamily.


Assuntos
Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/metabolismo , Morfogênese , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Animais , Repetição de Anquirina/genética , Células Cultivadas , Proteínas do Citoesqueleto/genética , Células HEK293 , Células HeLa , Humanos , Camundongos , Modelos Moleculares , Neurônios/citologia , Neurônios/metabolismo , Domínios Proteicos/genética , Ratos , Fatores de Transcrição/genética
20.
Genes Dev ; 33(17-18): 1117-1135, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481536

RESUMO

T-cell development in mammals is a model for lineage choice and differentiation from multipotent stem cells. Although T-cell fate choice is promoted by signaling in the thymus through one dominant pathway, the Notch pathway, it entails a complex set of gene regulatory network and chromatin state changes even before the cells begin to express their signature feature, the clonal-specific T-cell receptors (TCRs) for antigen. This review distinguishes three developmental modules for T-cell development, which correspond to cell type specification, TCR expression and selection, and the assignment of cells to different effector types. The first is based on transcriptional regulatory network events, the second is dominated by somatic gene rearrangement and mutation and cell selection, and the third corresponds to establishing a poised state of latent regulator priming through an unknown mechanism. Interestingly, in different lineages, the third module can be deployed at variable times relative to the completion of the first two modules. This review focuses on the gene regulatory network and chromatin-based kinetic constraints that determine activities of transcription factors TCF1, GATA3, PU.1, Bcl11b, Runx1, and E proteins in the primary establishment of T-cell identity.


Assuntos
Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Linfócitos T/citologia , Animais , Diferenciação Celular/genética , Linhagem da Célula , Cromatina/metabolismo , Redes Reguladoras de Genes , Hematopoese , Linfócitos T/metabolismo , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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