Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros

Banco de datos
Tipo de estudio
Tipo del documento
Asunto de la revista
País de afiliación
Intervalo de año de publicación
1.
Immunity ; 51(6): 1074-1087.e9, 2019 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-31784108

RESUMEN

Infections induce complex host responses linked to antiviral defense, inflammation, and tissue damage and repair. We hypothesized that the liver, as a central metabolic hub, may orchestrate systemic metabolic changes during infection. We infected mice with chronic lymphocytic choriomeningitis virus (LCMV), performed RNA sequencing and proteomics of liver tissue, and integrated these data with serum metabolomics at different infection phases. Widespread reprogramming of liver metabolism occurred early after infection, correlating with type I interferon (IFN-I) responses. Viral infection induced metabolic alterations of the liver that depended on the interferon alpha/beta receptor (IFNAR1). Hepatocyte-intrinsic IFNAR1 repressed the transcription of metabolic genes, including Otc and Ass1, which encode urea cycle enzymes. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8+ T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation. VIDEO ABSTRACT.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Interferón Tipo I/inmunología , Hígado/metabolismo , Virus de la Coriomeningitis Linfocítica/inmunología , Receptor de Interferón alfa y beta/metabolismo , Animales , Arginina/sangre , Línea Celular , Chlorocebus aethiops , Cricetinae , Femenino , Hepatocitos/metabolismo , Hígado/inmunología , Hígado/virología , Coriomeningitis Linfocítica/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ornitina/sangre , Ornitina Carbamoiltransferasa/genética , Transducción de Señal/inmunología , Urea/metabolismo , Células Vero
2.
Science ; 360(6390): 800-805, 2018 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-29622725

RESUMEN

Defining direct targets of transcription factors and regulatory pathways is key to understanding their roles in physiology and disease. We combined SLAM-seq [thiol(SH)-linked alkylation for the metabolic sequencing of RNA], a method for direct quantification of newly synthesized messenger RNAs (mRNAs), with pharmacological and chemical-genetic perturbation in order to define regulatory functions of two transcriptional hubs in cancer, BRD4 and MYC, and to interrogate direct responses to BET bromodomain inhibitors (BETis). We found that BRD4 acts as general coactivator of RNA polymerase II-dependent transcription, which is broadly repressed upon high-dose BETi treatment. At doses triggering selective effects in leukemia, BETis deregulate a small set of hypersensitive targets including MYC. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator controlling metabolic processes such as ribosome biogenesis and de novo purine synthesis. Our study establishes a simple and scalable strategy to identify direct transcriptional targets of any gene or pathway.


Asunto(s)
Antineoplásicos/farmacología , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Genes Reguladores , Leucemia Mieloide/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Proteínas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factores de Transcripción/metabolismo , Antineoplásicos/uso terapéutico , Proteínas de Ciclo Celular , Relación Dosis-Respuesta a Droga , Humanos , Leucemia Mieloide/genética , Terapia Molecular Dirigida , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas c-myc/genética , Purinas/biosíntesis , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ribosomas/metabolismo , Análisis de Secuencia de ARN , Factores de Transcripción/genética , Transcripción Genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA