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1.
J Leukoc Biol ; 100(4): 711-723, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27154355

RESUMEN

Oligodendrocyte transcription factor 2, a basic helix-loop-helix transcription factor that binds to E-box motifs, is known to have a key role in determining lineage specification of oligodendrocytes and motor neurons. In the present study, we report that oligodendrocyte transcription factor 2 is expressed in human eosinophils and involved in transcriptional activation of the gene encoding sialic acid binding immunoglobulin-like lectin 8 (Siglec-8), a late eosinophil-differentiation marker known to exert eosinophil apoptosis. When cord blood CD34+ hematopoietic stem cells differentiated toward eosinophils during a 24-d culture period, oligodendrocyte transcription factor 2 protein was expressed in cord blood eosinophils on d 24, a time when cord blood eosinophils are considered fully differentiated, whereas it was not detectable on d 18 or at earlier time points. Oligodendrocyte transcription factor 2 protein was also abundantly expressed in human peripheral-blood eosinophils but not in neutrophils, monocytes, lymphocytes, or cord blood mast cells. RNA sequencing analysis showed that numerous genes, especially those encoding eosinophil surface molecules, were highly up-regulated along with OLIG2 Among the genes examined, SIGLEC-8 messenger RNA and protein were markedly down-regulated in parallel with OLIG2 by an oligodendrocyte transcription factor 2 small interfering RNA or a short hairpin RNA, as evidenced by real-time polymerase chain reaction, fluorescence-activated cell sorting, and Western blot analyses. In reporter gene and chromatin immunoprecipitation experiments, an E-box in the first intron was found to stimulate SIGLEC-8 gene transcription and to bind oligodendrocyte transcription factor 2. Hence, at least one important aspect of eosinophil differentiation is regulated by oligodendrocyte transcription factor 2, a transcription factor that has not previously been reported, to our knowledge, in normal granulocytes.


Asunto(s)
Antígenos CD/biosíntesis , Antígenos de Diferenciación de Linfocitos B/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Eosinófilos/citología , Regulación del Desarrollo de la Expresión Génica , Lectinas/biosíntesis , Mielopoyesis/genética , Proteínas del Tejido Nervioso/fisiología , Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos B/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Células Cultivadas , Elementos E-Box/genética , Eosinófilos/metabolismo , Sangre Fetal/citología , Genes Reporteros , Células Madre Hematopoyéticas/citología , Humanos , Hipersensibilidad Inmediata/sangre , Intrones/genética , Lectinas/genética , Mastocitos/metabolismo , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Neutrófilos/metabolismo , Factor de Transcripción 2 de los Oligodendrocitos , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Interferente Pequeño/genética , Análisis de Secuencia de ARN
2.
Exp Mol Med ; 44(4): 268-80, 2012 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-22217447

RESUMEN

DNA methylation may regulate gene expression by restricting the access of transcription factors. We have previously demonstrated that GATA-1 regulates the transcription of the CCR3 gene by dynamically interacting with both positively and negatively acting GATA elements of high affinity binding in the proximal promoter region including exon 1. Exon 1 has three CpG sites, two of which are positioned at the negatively acting GATA elements. We hypothesized that the methylation of these two CpGs sites might preclude GATA-1 binding to the negatively acting GATA elements and, as a result, increase the availability of GATA-1 to the positively acting GATA element, thereby contributing to an increase in GATA-1-mediated transcription of the gene. To this end, we determined the methylation of the three CpG sites by bisulfate pyrosequencing in peripheral blood eosinophils, cord blood (CB)-derived eosinophils, PBMCs, and cell lines that vary in CCR3 mRNA expression. Our results demonstrated that methylation of CpG sites at the negatively acting GATA elements severely reduced GATA-1 binding and augmented transcription activity in vitro. In agreement, methylation of these CpG sites positively correlated with CCR3 mRNA expression in the primary cells and cell lines examined. Interestingly, methylation patterns of these three CpG sites in CB-derived eosinophils mostly resembled those in peripheral blood eosinophils. These results suggest that methylation of CpG sites at the GATA elements in the regulatory regions fine-tunes CCR3 transcription.


Asunto(s)
Islas de CpG , Eosinófilos/metabolismo , Factor de Transcripción GATA1/genética , Receptores CCR3/genética , Transcripción Genética , Sitios de Unión , Línea Celular , Metilación de ADN , Elementos de Facilitación Genéticos , Eosinófilos/citología , Exones , Sangre Fetal/citología , Sangre Fetal/metabolismo , Factor de Transcripción GATA1/metabolismo , Regulación de la Expresión Génica , Humanos , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo , Receptores CCR3/metabolismo , Análisis de Secuencia de ADN
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