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1.
Nat Commun ; 11(1): 4980, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020477

RESUMO

The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as "Yin and Yang" partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14ARF in human and p19ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst diverse cancer types and is shown to support cell survival, division and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53.


Assuntos
Neoplasias/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Longo não Codificante/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Carcinogênese , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , RNA Longo não Codificante/genética , Sumoilação , Proteína Supressora de Tumor p53/genética , Ubiquitinação
2.
Nat Commun ; 11(1): 5063, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033242

RESUMO

Genome-wide chromatin state underlies gene expression potential and cellular function. Epigenetic features and nucleosome positioning contribute to the accessibility of DNA, but widespread regulators of chromatin state are largely unknown. Our study investigates how coordination of ANP32E and H2A.Z contributes to genome-wide chromatin state in mouse fibroblasts. We define H2A.Z as a universal chromatin accessibility factor, and demonstrate that ANP32E antagonizes H2A.Z accumulation to restrict chromatin accessibility genome-wide. In the absence of ANP32E, H2A.Z accumulates at promoters in a hierarchical manner. H2A.Z initially localizes downstream of the transcription start site, and if H2A.Z is already present downstream, additional H2A.Z accumulates upstream. This hierarchical H2A.Z accumulation coincides with improved nucleosome positioning, heightened transcription factor binding, and increased expression of neighboring genes. Thus, ANP32E dramatically influences genome-wide chromatin accessibility through subtle refinement of H2A.Z patterns, providing a means to reprogram chromatin state and to hone gene expression levels.


Assuntos
Cromatina/metabolismo , Genoma , Chaperonas Moleculares/metabolismo , Animais , Diferenciação Celular/genética , DNA Helicases/metabolismo , Embrião de Mamíferos/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Histonas/metabolismo , Camundongos , Proteínas Nucleares/metabolismo , Nucleossomos/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Fatores de Transcrição/metabolismo
3.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2471-2474, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018507

RESUMO

HPV infection starts with the activation of the early promoter (EP) regulatory core and the replication of the viral particles to around 10-100 per cell at the beginning of the infection. For this reason, understanding the deterministic and stochastic role of the population number of viruses inside the cell is of pivotal importance to understand the regulation of the EP and the viral latency.The aim of this study is to extend a recently published minimal model of the EP transcriptional regulation in order to consider the effect of the viral population on gene regulation, to perform the bifurcation analysis and to understand the role of the stochasticity at the beginning of the infection.The bifurcation analysis showed how modeling the viral population number is pivotal to exhibit a bistable behavior, potentially linked to the viral latency. Moreover, the viral population number was identified as an important source of stochasticity, which is of paramount importance to drive the bistable switching mechanism in the first stages of infection.


Assuntos
Papillomaviridae , Infecções por Papillomavirus , Regulação Viral da Expressão Gênica , Humanos , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Regiões Promotoras Genéticas , Latência Viral
4.
Nat Commun ; 11(1): 5061, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033262

RESUMO

The interplay between the Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) and transcriptional/epigenetic co-regulators in somatic cell reprogramming is incompletely understood. Here, we demonstrate that the histone H3 lysine 27 trimethylation (H3K27me3) demethylase JMJD3 plays conflicting roles in mouse reprogramming. On one side, JMJD3 induces the pro-senescence factor Ink4a and degrades the pluripotency regulator PHF20 in a reprogramming factor-independent manner. On the other side, JMJD3 is specifically recruited by KLF4 to reduce H3K27me3 at both enhancers and promoters of epithelial and pluripotency genes. JMJD3 also promotes enhancer-promoter looping through the cohesin loading factor NIPBL and ultimately transcriptional elongation. This competition of forces can be shifted towards improved reprogramming by using early passage fibroblasts or boosting JMJD3's catalytic activity with vitamin C. Our work, thus, establishes a multifaceted role for JMJD3, placing it as a key partner of KLF4 and a scaffold that assists chromatin interactions and activates gene transcription.


Assuntos
Reprogramação Celular , Histona Desmetilases com o Domínio Jumonji/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Animais , Catálise , Proliferação de Células , Senescência Celular , Desmetilação , Elementos Facilitadores Genéticos/genética , Células Epiteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genoma , Histonas/metabolismo , Lisina/metabolismo , Camundongos , Modelos Biológicos , Regiões Promotoras Genéticas , Ativação Transcricional/genética
5.
Nat Commun ; 11(1): 5078, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033266

RESUMO

Metabolic engineering facilitates chemical biosynthesis by rewiring cellular resources to produce target compounds. However, an imbalance between cell growth and bioproduction often reduces production efficiency. Genetic code expansion (GCE)-based orthogonal translation systems incorporating non-canonical amino acids (ncAAs) into proteins by reassigning non-canonical codons to ncAAs qualify for balancing cellular metabolism. Here, GCE-based cell growth and biosynthesis balance engineering (GCE-CGBBE) is developed, which is based on titrating expression of cell growth and metabolic flux determinant genes by constructing ncAA-dependent expression patterns. We demonstrate GCE-CGBBE in genome-recoded Escherichia coli Δ321AM by precisely balancing glycolysis and N-acetylglucosamine production, resulting in a 4.54-fold increase in titer. GCE-CGBBE is further expanded to non-genome-recoded Bacillus subtilis to balance growth and N-acetylneuraminic acid bioproduction by titrating essential gene expression, yielding a 2.34-fold increase in titer. Moreover, the development of ncAA-dependent essential gene expression regulation shows efficient biocontainment of engineered B. subtilis to avoid unintended proliferation in nature.


Assuntos
Acetilglucosamina/metabolismo , Bacillus subtilis/crescimento & desenvolvimento , Vias Biossintéticas , Escherichia coli/crescimento & desenvolvimento , Ácido N-Acetilneuramínico/metabolismo , Bacillus subtilis/metabolismo , Proliferação de Células , Escherichia coli/metabolismo , Código Genético , Proteínas de Fluorescência Verde/metabolismo , Engenharia Metabólica , Análise do Fluxo Metabólico , Regiões Promotoras Genéticas/genética , RNA de Transferência/genética , Tirosina/metabolismo
6.
Medicine (Baltimore) ; 99(38): e22278, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957381

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is a multifactorial disease with gene-environment interaction resulting in progressive renal function damage. Multiple studies have assessed the association between matrix metalloproteinase-9 (MMP-9) gene promoter polymorphism and DN susceptibility. However, the results are inconclusive. In the present study, we will conduct a meta-analysis to further examine this relationship more precisely. METHODS: Electronic databases (Pubmed, Web of Science, Embase, Google Scholar, Wanfang, China Biological Medicine and China National Knowledge Infrastructure) will be used to search clinical case-control studies about MMP-9 polymorphism and DN published until 18 August 2020. The language will be restricted to Chinese and English. Two reviewers will take charge of completing the selection of study, the extraction of data as well as the assessment of study quality independently. The Newcastle-Ottawa Scale will be used to evaluate the study quality. We will evaluate the association under 5 genetic models. Fixed-effects or random-effects models will be used to calculate the effect sizes of odds ratio and 95% confidence intervals. Afterwards, subgroup analysis will be conducted in terms of the ethnicity and genotyping method. Additionally, sensitivity analysis will be performed via sequentially omitting each of the included studies one at a time. The funnel plots, Egger regression test, and Begg rank correlation test will be used to test the potential publication bias. All the statistical analyses will be performed using Review Manager 5.3 and Stata 12.0. RESULTS: This protocol reported according to the Preferred Reporting ltems for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement. This study will provide a better understanding of the association between MMP-9 polymorphisms and DN risk. CONCLUSION: Publishing this protocol will minimize the potential bias related to data mining, thus contributing to generation of reliable evidence. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/H5FS4.


Assuntos
Nefropatias Diabéticas/genética , Metaloproteinase 9 da Matriz/genética , Metanálise como Assunto , Polimorfismo Genético , Revisões Sistemáticas como Assunto , Nefropatias Diabéticas/enzimologia , Predisposição Genética para Doença , Humanos , Regiões Promotoras Genéticas/genética , Fatores de Risco
7.
PLoS Pathog ; 16(9): e1008834, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956422

RESUMO

Despite the widespread use of anti-retroviral therapy, human immunodeficiency virus (HIV) still persists in an infected cell reservoir that harbors transcriptionally silent yet replication-competent proviruses. While significant progress has been made in understanding how the HIV reservoir is established, transcription repression mechanisms that are enforced on the integrated viral promoter have not been fully revealed. In this study, we performed a whole-genome CRISPR knockout screen in HIV infected T cells to identify host genes that potentially promote HIV latency. Of several top candidates, the KRAB-containing zinc finger protein, ZNF304, was identified as the top hit. ZNF304 silences HIV gene transcription through associating with TRIM28 and recruiting to the viral promoter heterochromatin-inducing methyltransferases, including the polycomb repression complex (PRC) and SETB1. Depletion of ZNF304 expression reduced levels of H3K9me3, H3K27me3 and H2AK119ub repressive histone marks on the HIV promoter as well as SETB1 and TRIM28, ultimately enhancing HIV gene transcription. Significantly, ZNF304 also promoted HIV latency, as its depletion delayed the entry of HIV infected cells into latency. In primary CD4+ cells, ectopic expression of ZNF304 silenced viral transcription. We conclude that by associating with TRIM28 and recruiting host transcriptional repressive complexes, SETB1 and PRC, to the HIV promoter, ZNF304 silences HIV gene transcription and promotes viral latency.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Regulação Viral da Expressão Gênica , Inativação Gênica , HIV-1/fisiologia , Proteínas Repressoras , Fatores de Transcrição , Transcrição Genética , Latência Viral , Linfócitos T CD4-Positivos/virologia , Sistemas CRISPR-Cas , Técnicas de Inativação de Genes , Estudo de Associação Genômica Ampla , Humanos , Células Jurkat , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína 28 com Motivo Tripartido/genética , Proteína 28 com Motivo Tripartido/metabolismo
8.
Nat Commun ; 11(1): 4782, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963223

RESUMO

Polycomb and Trithorax group proteins maintain stable epigenetic memory of gene expression states for some genes, but many targets show highly dynamic regulation. Here we combine experiment and theory to examine the mechanistic basis of these different modes of regulation. We present a mathematical model comprising a Polycomb/Trithorax response element (PRE/TRE) coupled to a promoter and including Drosophila developmental timing. The model accurately recapitulates published studies of PRE/TRE mediated epigenetic memory of both silencing and activation. With minimal parameter changes, the same model can also recapitulate experimental data for a different PRE/TRE that allows dynamic regulation of its target gene. The model predicts that both cell cycle length and PRE/TRE identity are critical for determining whether the system gives stable memory or dynamic regulation. Our work provides a simple unifying framework for a rich repertoire of PRE/TRE functions, and thus provides insights into  genome-wide Polycomb/Trithorax regulation.


Assuntos
Proteínas Cromossômicas não Histona/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Epigenômica , Regulação da Expressão Gênica no Desenvolvimento/genética , Modelos Teóricos , Complexo Repressor Polycomb 1/genética , Animais , Divisão Celular , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Epigênese Genética , Feminino , Inativação Gênica , Complexo Repressor Polycomb 1/metabolismo , Proteínas do Grupo Polycomb/metabolismo , Regiões Promotoras Genéticas , Elementos de Resposta
9.
Zhonghua Zhong Liu Za Zhi ; 42(8): 644-647, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867455

RESUMO

Objective: To explore the application value of lung cancer-related gene methylation in lung cancer diagnosis. Methods: Sixty patients with lung cancer underwent surgery were selected as the case group, and 65 patients with benign lung lesions treated in the same period were recruited as the control group. The methylation levels of lung cancer-related genes including dying-associated protein kinase (DAPK), O-6-methylguanine-DNA methyltransferase (MGMT), APC gene promoter 1A (APC1A) and epithelial mucoprotein gene (ECAD) in the blood samples of two groups of patients were analyzed by methylated PCR-specific method. The relationship between methylation of lung cancer-related genes and lung cancer was analyzed and its diagnostic value in lung cancer was evaluated. Results: The methylation detection rates of DAPK, MGMT, APC1A and ECAD in the case group were 68.3%, 68.3%, 63.3% and 65.0%, respectively, all higher than those of the control group (all P<0.05). The multivariate Logistic regression analysis showed that DAPK (OR=0.709), MGMT (OR=0.793), APC1A (OR=0.163), and ECAD (OR=2.047) were all independent influencing factors for lung cancer (all P<0.05). Analysis of the receiver operating characteristic curve showed that, the area under the curve (AUC) of DAPK, MGMT, APC1A and ECAD methylation test for lung cancer predicting were 0.623, 0.680, 0.620 and 0.648, respectively, while the AUC of the combined four gene methylation for lung cancer predicting was 0.829, higher than the AUC of each gene (all P<0.05). Conclusion: The combined methylation detection of multiple lung cancer related genes can improve the diagnostic value of lung cancer, contribute to the early diagnosis of lung cancer, and have potentially clinical application value.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA , Proteínas Quinases Associadas com Morte Celular/genética , Neoplasias Pulmonares/diagnóstico , O(6)-Metilguanina-DNA Metiltransferase/genética , Regiões Promotoras Genéticas/genética , Estudos de Casos e Controles , Detecção Precoce de Câncer , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Genética
10.
Anticancer Res ; 40(10): 5503-5508, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988873

RESUMO

BACKGROUND/AIM: Accumulating evidence shows that caspase-8 (Cas-8) rs3834129 genotypes determine susceptibility to various cancers, but their association with nasopharyngeal carcinoma (NPC) has not been examined. We aimed at investigating the association of Cas-8 rs3834129 with NPC risk. MATERIALS AND METHODS: Cas-8 rs3834129 genotypes and their associations with NPC risk were investigated among 176 NPC patients and 352 non-cancer subjects by the PCR-RFLP method. Additionally, the interaction of Cas-8 rs3834129 genotypes with smoking was examined. RESULTS: The II, ID and DD frequencies were 56.8, 36.9 and 6.3% among NPC patients and 54.8, 38.1 and 7.1% among control subjects (ptrend=0.8830). Allelic frequency distribution analysis also indicated that the D allele is not a risk factor for NPC (p=0.6183). There was no interaction between Cas-8 rs3834129 and smoking and NPC risk (p=0.8305). CONCLUSION: Cas-8 rs3834129 genotypes play a minor role in the risk for NPC.


Assuntos
Caspase 8/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Carcinoma Nasofaríngeo/genética , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/epidemiologia , Carcinoma Nasofaríngeo/patologia , Polimorfismo de Fragmento de Restrição/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Fatores de Risco , Fumar , Taiwan
11.
Anticancer Res ; 40(10): 5751-5756, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988902

RESUMO

BACKGROUND/AIM: A single study has shown positive association and genotype-phenotype correlation between metalloproteinase-9 (MMP-9) promoter genotypes and adult acute lymphocytic leukemia (ALL). However, there is no report about childhood ALL. Thus, this study aimed at examining the role of MMP-9 rs3918242 genotypes in childhood ALL risk. PATIENTS AND METHODS: A total of 266 childhood ALL cases and 266 healthy controls in Taiwan were examined for their MMP-9 rs3918242 genotypes via polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The MMP-9 rs3918242 CT or TT genotype carriers only had a slightly increased risk compared with CC carriers (p=0.6386 and 0.6005, respectively). The allelic frequency analysis also supported the idea that the variant T allele at MMP-9 rs3918242 is not differentially distributed between the case and control groups (p=0.4834). CONCLUSION: MMP-9 rs3918242 genotypes may indirectly influence the risk of childhood ALL. Further validations in other populations and analysis of the detail mechanisms are needed.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Metaloproteinase 9 da Matriz/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Alelos , Criança , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Regiões Promotoras Genéticas/genética
12.
Ecotoxicol Environ Saf ; 203: 111031, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888610

RESUMO

Bone mineral density (BMD) changes were reported to be associated with excessive fluoride exposure and abnormal expression of RUNX2. However, whether the alteration of methylation status, a most commonly used marker for the alteration of gene expression in epidemiological investigation, of RUNX2 is associated with low-to-moderate fluoride exposure and BMD changes has not been reported. Our study aims to explore the role of RUNX2 promoter methylation in BMD changes induced by low-to-moderate fluoride exposure. A total of 1124 adults (413 men and 711 women) were recruited from Kaifeng City in 2017. We measured BMD using ultrasound bone densitometer. Concentrations of urinary fluoride (UF) were measured using ion-selective electrode, and the participants were grouped into control group (CG) and excessive fluoride group (EFG) according to the concentration of UF. We extracted DNA from fasting peripheral blood samples and then detected the promoter methylation levels of RUNX2 using quantitative methylation-specific PCR. Relationships between UF concentration, RUNX2 promoter methylation and BMD changes were analyzed using generalized linear model and logistic regression. Results showed in EFG (UF concentration > 1.6 mg/L), BMD was negatively correlated with UF concentration (ß: -0.14; 95%CI: -0.26, -0.01) and RUNX2 promoter methylation (ß: -0.13; 95%CI: -0.22, -0.03) in women. The methylation rate of RUNX2 promoter increased by 2.16% for each 1 mg/L increment in UF concentration of women in EFG (95%CI: 0.37, 3.96). No any significant associations between UF concentration, RUNX2 promoter methylation, and BMD were observed in the individuals in CG. Mediation analysis showed that RUNX2 promoter methylation mediated 18.2% (95% CI: 4.2%, 53.2%) of the association between UF concentration and BMD of women in EFG. In conclusion, excessive fluoride exposure (>1.6 mg/L) is associated with changes of BMD in women, and this association is mediated by RUNX2 promoter methylation.


Assuntos
Densidade Óssea/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Exposição Ambiental/análise , Fluoretos/toxicidade , Poluentes Químicos da Água/toxicidade , Absorciometria de Fóton , Adulto , Idoso , Densidade Óssea/genética , China , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Estudos Transversais , Metilação de DNA/efeitos dos fármacos , Feminino , Fluoretos/urina , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Inquéritos e Questionários , Poluentes Químicos da Água/urina
13.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(9): 980-983, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-32933630

RESUMO

OBJECTIVE: To study the expression level of cAMP response element-binding protein (CREB) in children with recurrent wheezing under three years of age and its effect on the expression of the serum orosomucoid 1-like protein 3 (ORMDL3) gene. METHODS: Thirty-six children with recurrent wheezing under three years of age who visited the hospital from June 2017 to June 2019 were selected as the recurrent wheezing group. Twenty-four healthy children from physical examination were selected as the control group. The CREB expression level in peripheral blood was measured by quantitative real-time PCR. Human bronchial epithelial cells (BEAS-2B) were cultured, and dual-luciferase reporter assay and quantitative real-time PCR were used to investigate the effects of overexpression and siRNA interference of CREB on the promoter activity and mRNA expression of the ORMDL3 gene in the BEAS-2B cells. RESULTS: The expression level of CREB in the recurrent wheezing group was significantly higher than that in the control group (P<0.001). In BEAS-2B cells, overexpression of CREB significantly up-regulated the promoter activity and mRNA expression of the ORMDL3 gene (P<0.05), while siRNA interference of CREB significantly reduced the promoter activity and mRNA expression of the ORMDL3 gene (P<0.05). CONCLUSIONS: The expression of CREB is increased in children with recurrent wheezing, and CREB may be involved in the pathogenesis of recurrent wheezing by regulating expression of the ORMDL3 gene.


Assuntos
Proteínas de Membrana/genética , Sons Respiratórios , Pré-Escolar , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Células Epiteliais , Humanos , Regiões Promotoras Genéticas
14.
Nature ; 585(7825): 459-463, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908305

RESUMO

The RNA polymerase II (Pol II) core promoter is the strategic site of convergence of the signals that lead to the initiation of DNA transcription1-5, but the downstream core promoter in humans has been difficult to understand1-3. Here we analyse the human Pol II core promoter and use machine learning to generate predictive models for the downstream core promoter region (DPR) and the TATA box. We developed a method termed HARPE (high-throughput analysis of randomized promoter elements) to create hundreds of thousands of DPR (or TATA box) variants, each with known transcriptional strength. We then analysed the HARPE data by support vector regression (SVR) to provide comprehensive models for the sequence motifs, and found that the SVR-based approach is more effective than a consensus-based method for predicting transcriptional activity. These results show that the DPR is a functionally important core promoter element that is widely used in human promoters. Notably, there appears to be a duality between the DPR and the TATA box, as many promoters contain one or the other element. More broadly, these findings show that functional DNA motifs can be identified by machine learning analysis of a comprehensive set of sequence variants.


Assuntos
Sequência Consenso/genética , Regulação da Expressão Gênica/genética , Regiões Promotoras Genéticas/genética , RNA Polimerase II/metabolismo , Máquina de Vetores de Suporte , Transcrição Genética , Sequência de Bases , Células/metabolismo , Simulação por Computador , Conjuntos de Dados como Assunto , Células HeLa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Genéticos , Mutagênese , TATA Box/genética
15.
PLoS Pathog ; 16(9): e1008552, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32966346

RESUMO

Type VI secretion systems (T6SSs) are complex macromolecular injection machines which are widespread in Gram-negative bacteria. They are involved in host-cell interactions and pathogenesis, required to eliminate competing bacteria, or are important for the adaptation to environmental stress conditions. Here we identified regulatory elements controlling the T6SS4 of Yersinia pseudotuberculosis and found a novel type of hexameric transcription factor, RovC. RovC directly interacts with the T6SS4 promoter region and activates T6SS4 transcription alone or in cooperation with the LysR-type regulator RovM. A higher complexity of regulation was achieved by the nutrient-responsive global regulator CsrA, which controls rovC expression on the transcriptional and post-transcriptional level. In summary, our work unveils a central mechanism in which RovC, a novel key activator, orchestrates the expression of the T6SS weapons together with a global regulator to deploy the system in response to the availability of nutrients in the species' native environment.


Assuntos
Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Regiões Promotoras Genéticas , Sistemas de Secreção Tipo VI/metabolismo , Yersinia pseudotuberculosis/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Conformação Proteica , Estresse Fisiológico , Sistemas de Secreção Tipo VI/química , Sistemas de Secreção Tipo VI/genética , Yersinia pseudotuberculosis/genética
16.
Nat Commun ; 11(1): 4457, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901017

RESUMO

Innate lymphoid cells (ILCs) and CD4+ T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4+ T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4+ T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4+ T cells and ILCs to maintain intestinal homeostasis.


Assuntos
Ácidos Graxos Voláteis/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Interleucinas/biossíntese , Animais , Butiratos/imunologia , Butiratos/metabolismo , Butiratos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Citrobacter rodentium , Colite/imunologia , Colite/microbiologia , Colite/prevenção & controle , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/prevenção & controle , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/farmacologia , Microbioma Gastrointestinal/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Técnicas In Vitro , Interleucinas/deficiência , Interleucinas/genética , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
17.
Nat Commun ; 11(1): 4544, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917861

RESUMO

Stratification of enhancers by signal strength in ChIP-seq assays has resulted in the establishment of super-enhancers as a widespread and useful tool for identifying cell type-specific, highly expressed genes and associated pathways. We examine a distinct method of stratification that focuses on peak breadth, termed hyperacetylated chromatin domains (HCDs), which classifies broad regions exhibiting histone modifications associated with gene activation. We find that this analysis serves to identify genes that are both more highly expressed and more closely aligned to cell identity than super-enhancer analysis does using multiple data sets. Moreover, genetic manipulations of selected gene loci suggest that some enhancers located within HCDs work at least in part via a distinct mechanism involving the modulation of histone modifications across domains and that this activity can be imported into a heterologous gene locus. In addition, such genetic dissection reveals that the super-enhancer concept can obscure important functions of constituent elements.


Assuntos
Cromatina/metabolismo , Elementos Facilitadores Genéticos/genética , Loci Gênicos/genética , Ativação Transcricional , Acetilação , Animais , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Sequenciamento de Cromatina por Imunoprecipitação , Conjuntos de Dados como Assunto , Embrião de Mamíferos , Eritroblastos , Feminino , Feto , Código das Histonas/genética , Histonas/genética , Histonas/metabolismo , Humanos , Camundongos , Regiões Promotoras Genéticas/genética , RNA-Seq
18.
Nat Commun ; 11(1): 4634, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929078

RESUMO

The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.


Assuntos
Cromatina/metabolismo , Corpo Estriado/enzimologia , Dependência de Heroína/enzimologia , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Animais , Sequência de Bases , Comportamento Animal/efeitos dos fármacos , Sinais (Psicologia) , Genoma , Células HEK293 , Heroína/efeitos adversos , Humanos , Masculino , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-fyn/antagonistas & inibidores , Ratos Long-Evans , Autoadministração , Transcrição Genética/efeitos dos fármacos , Proteínas tau/metabolismo
19.
Nat Commun ; 11(1): 4664, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938919

RESUMO

Cardiorenal syndrome type 4 (CRS4) is a common complication of chronic kidney disease (CKD), but the pathogenic mechanisms remain elusive. Here we report that morphological and functional changes in myocardial mitochondria are observed in CKD mice, especially decreases in oxidative phosphorylation and fatty acid metabolism. High phosphate (HP), a hallmark of CKD, contributes to myocardial energy metabolism dysfunction by downregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α). Furthermore, the transcriptional factor interferon regulatory factor 1 (IRF1) is revealed as the key molecule upregulated by HP through histone H3K9 acetylation, and responsible for the HP-mediated transcriptional inhibition of PGC1α by directly binding to its promoter region. Conversely, restoration of PGC1α expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4.


Assuntos
Síndrome Cardiorrenal/metabolismo , Fator Regulador 1 de Interferon/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Síndrome Cardiorrenal/patologia , Modelos Animais de Doenças , Regulação para Baixo , Metabolismo Energético , Técnicas de Silenciamento de Genes , Taxa de Filtração Glomerular , Glucuronidase/genética , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Humanos , Fator Regulador 1 de Interferon/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fosfatos/metabolismo , Regiões Promotoras Genéticas , Ratos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Adulto Jovem
20.
Adv Exp Med Biol ; 1255: 123-132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949395

RESUMO

Hypermethylation can downregulate many tumor suppressor gene expressions. Aplasia Ras homologue member I (ARHI, DIRAS3) is one of the maternally imprinted tumor suppressors in the RAS superfamily. This chapter overviewed the importance of ARHI methylation and expression phenomes in various types of cancers, although the exact mechanisms remain unclear. As an imprinted gene, aberrant DNA methylation of the paternal allele of ARHI was identified as a primary inhibitor of ARHI expression. The role of methylation in the CpG islands of the ARHI promoter region vary among ovarian cancers, breast cancers, hepatocellular carcinoma, colon cancers, pancreatic cancer osteosarcoma, glial tumors, follicular thyroid carcinoma, or lung cancers. The methylation of ARHI provides a new insight to understand molecular mechanisms of tumorigenesis and progression of cancers.


Assuntos
Ilhas de CpG/genética , Metilação de DNA , Neoplasias/genética , Regiões Promotoras Genéticas , Proteínas rho de Ligação ao GTP/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Humanos
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