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1.
Mol Cell ; 59(6): 984-97, 2015 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-26321255

RESUMO

Transcriptionally active and inactive chromatin domains tend to segregate into separate sub-nuclear compartments to maintain stable expression patterns. However, here we uncovered an inter-chromosomal network connecting active loci enriched in circadian genes to repressed lamina-associated domains (LADs). The interactome is regulated by PARP1 and its co-factor CTCF. They not only mediate chromatin fiber interactions but also promote the recruitment of circadian genes to the lamina. Synchronization of the circadian rhythm by serum shock induces oscillations in PARP1-CTCF interactions, which is accompanied by oscillating recruitment of circadian loci to the lamina, followed by the acquisition of repressive H3K9me2 marks and transcriptional attenuation. Furthermore, depletion of H3K9me2/3, inhibition of PARP activity by olaparib, or downregulation of PARP1 or CTCF expression counteracts both recruitment to the envelope and circadian transcription. PARP1- and CTCF-regulated contacts between circadian loci and the repressive chromatin environment at the lamina therefore mediate circadian transcriptional plasticity.


Assuntos
Cromatina/genética , Células-Tronco Embrionárias Humanas/enzimologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Repressoras/metabolismo , Transcrição Gênica , Proteínas Adaptadoras de Transdução de Sinal , Fator de Ligação a CCCTC , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Imunoprecipitação da Cromatina , Ritmo Circadiano , Corpos Embrioides/enzimologia , Epistasia Genética , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Células HCT116 , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Lâmina Nuclear/metabolismo , Poli(ADP-Ribose) Polimerase-1 , Ligação Proteica , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
2.
Cell Microbiol ; 16(8): 1244-54, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24612488

RESUMO

ExoU is an important virulence factor in acute Pseudomonas aeruginosa infections. Here, we unveiled the mechanisms of ExoU-driven NF-κB activation by using human airway cells and mice infected with P. aeruginosa strains. Several approaches showed that PAFR was crucially implicated in the activation of the canonical NF-κB pathway. Confocal microscopy of lungs from infected mice revealed that PAFR-dependent NF-κB activation occurred mainly in respiratory epithelial cells, and reduced p65 nuclear translocation was detected in mice PAFR-/- or treated with the PAFR antagonist WEB 2086. Several evidences showed that ExoU-induced NF-κB activation regulated PAFR expression. First, ExoU increased p65 occupation of PAFR promoter, as assessed by ChIP. Second, luciferase assays in cultures transfected with different plasmid constructs revealed that ExoU promoted p65 binding to the three κB sites in PAFR promoter. Third, treatment of cell cultures with the NF-κB inhibitor Bay 11-7082, or transfection with IκBα negative-dominant, significantly decreased PAFR mRNA. Finally, reduction in PAFR expression was observed in mice treated with Bay 11-7082 or WEB 2086 prior to infection. Together, our data demonstrate that ExoU activates NF-κB by PAFR signalling, which in turns enhances PAFR expression, highlighting an important mechanism of amplification of response to this P. aeruginosa toxin.


Assuntos
Proteínas de Bactérias/metabolismo , Fator de Ativação de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/genética , Pseudomonas aeruginosa/patogenicidade , Receptores Acoplados a Proteínas G/genética , Fator de Transcrição RelA/metabolismo , Animais , Azepinas/farmacologia , Toxinas Bacterianas/metabolismo , Linhagem Celular , Ativação Enzimática , Feminino , Regulação da Expressão Gênica , Humanos , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Fator de Ativação de Plaquetas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Glicoproteínas da Membrana de Plaquetas/biossíntese , Regiões Promotoras Genéticas , Ligação Proteica , Infecções por Pseudomonas/patologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/biossíntese , Transdução de Sinais/genética , Triazóis/farmacologia
3.
Nat Commun ; 13(1): 204, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017527

RESUMO

Abnormal WNT signaling increases MYC expression in colon cancer cells in part via oncogenic super-enhancer-(OSE)-mediated gating of the active MYC to the nuclear pore in a poorly understood process. We show here that the principal tenet of the WNT-regulated MYC gating, facilitating nuclear export of the MYC mRNA, is regulated by a CTCF binding site (CTCFBS) within the OSE to confer growth advantage in HCT-116 cells. To achieve this, the CTCFBS directs the WNT-dependent trafficking of the OSE to the nuclear pore from intra-nucleoplasmic positions in a stepwise manner. Once the OSE reaches a peripheral position, which is triggered by a CTCFBS-mediated CCAT1 eRNA activation, its final stretch (≤0.7 µm) to the nuclear pore requires the recruitment of AHCTF1, a key nucleoporin, to the CTCFBS. Thus, a WNT/ß-catenin-AHCTF1-CTCF-eRNA circuit enables the OSE to promote pathological cell growth by coordinating the trafficking of the active MYC gene within the 3D nuclear architecture.


Assuntos
Fator de Ligação a CCCTC/genética , Proteínas de Ligação a DNA/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Via de Sinalização Wnt/genética , Transporte Ativo do Núcleo Celular , Sítios de Ligação , Fator de Ligação a CCCTC/metabolismo , Núcleo Celular/metabolismo , Colo/metabolismo , Colo/patologia , Citosol/metabolismo , Proteínas de Ligação a DNA/metabolismo , Elementos Facilitadores Genéticos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Células HCT116 , Humanos , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Genoma
4.
Science ; 359(6381): 1212-1213, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29590061
5.
Microbes Infect ; 12(2): 154-61, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19931407

RESUMO

ExoU, a Pseudomonas aeruginosa cytotoxin injected via the type III secretion system into host cells, possesses eicosanoid-mediated proinflammatory properties due to its phospholipase A(2) (PLA(2)) activity. This report addressed the question whether ExoU may modulate the expression of adhesion molecules in host cells, therefore contributing to the recruitment of leukocyte into infected tissues. ExoU was shown to down-regulate membrane-bound ICAM-1 (mICAM-1) and up-regulate the release of soluble ICAM-1 (sICAM-1) from P. aeruginosa-infected endothelial cells. The modulation of ICAM-1 depended on the direct effect of the ExoU PLA(2) activity and involved the cyclooxygenase (COX) pathway. No differences in mICAM-1 and sICAM-1 mRNA levels were observed when cultures were infected with the ExoU-producing PA103 strain or the mutant PA103DeltaexoU, suggesting that ExoU may proteolytically cleave mICAM-1, producing sICAM-1 in a COX-dependent pathway.


Assuntos
Proteínas de Bactérias/metabolismo , Células Endoteliais/microbiologia , Endotélio Vascular/microbiologia , Molécula 1 de Adesão Intercelular/metabolismo , Leucocidinas/metabolismo , Pseudomonas aeruginosa/patogenicidade , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , Molécula 1 de Adesão Intercelular/genética , Lipoxigenase/metabolismo , Pseudomonas aeruginosa/metabolismo
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