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1.
Nat Immunol ; 20(5): 546-558, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30911105

RESUMEN

Neutrophils are essential first-line defense cells against invading pathogens, yet when inappropriately activated, their strong immune response can cause collateral tissue damage and contributes to immunological diseases. However, whether neutrophils can intrinsically titrate their immune response remains unknown. Here we conditionally deleted the Spi1 gene, which encodes the myeloid transcription factor PU.1, from neutrophils of mice undergoing fungal infection and then performed comprehensive epigenomic profiling. We found that as well as providing the transcriptional prerequisite for eradicating pathogens, the predominant function of PU.1 was to restrain the neutrophil defense by broadly inhibiting the accessibility of enhancers via the recruitment of histone deacetylase 1. Such epigenetic modifications impeded the immunostimulatory AP-1 transcription factor JUNB from entering chromatin and activating its targets. Thus, neutrophils rely on a PU.1-installed inhibitor program to safeguard their epigenome from undergoing uncontrolled activation, protecting the host against an exorbitant innate immune response.


Asunto(s)
Epigénesis Genética/inmunología , Epigenómica/métodos , Neutrófilos/inmunología , Proteínas Proto-Oncogénicas/inmunología , Transactivadores/inmunología , Animales , Candida albicans/inmunología , Candida albicans/fisiología , Candidiasis/genética , Candidiasis/inmunología , Candidiasis/microbiología , Resistencia a la Enfermedad/genética , Resistencia a la Enfermedad/inmunología , Perfilación de la Expresión Génica/métodos , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neutrófilos/metabolismo , Neutrófilos/microbiología , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Análisis de Supervivencia , Transactivadores/deficiencia , Transactivadores/genética , Transcriptoma/genética , Transcriptoma/inmunología
2.
Nucleic Acids Res ; 50(14): 7938-7958, 2022 08 12.
Artículo en Inglés | MEDLINE | ID: mdl-35871293

RESUMEN

Although originally described as transcriptional activator, SPI1/PU.1, a major player in haematopoiesis whose alterations are associated with haematological malignancies, has the ability to repress transcription. Here, we investigated the mechanisms underlying gene repression in the erythroid lineage, in which SPI1 exerts an oncogenic function by blocking differentiation. We show that SPI1 represses genes by binding active enhancers that are located in intergenic or gene body regions. HDAC1 acts as a cooperative mediator of SPI1-induced transcriptional repression by deacetylating SPI1-bound enhancers in a subset of genes, including those involved in erythroid differentiation. Enhancer deacetylation impacts on promoter acetylation, chromatin accessibility and RNA pol II occupancy. In addition to the activities of HDAC1, polycomb repressive complex 2 (PRC2) reinforces gene repression by depositing H3K27me3 at promoter sequences when SPI1 is located at enhancer sequences. Moreover, our study identified a synergistic relationship between PRC2 and HDAC1 complexes in mediating the transcriptional repression activity of SPI1, ultimately inducing synergistic adverse effects on leukaemic cell survival. Our results highlight the importance of the mechanism underlying transcriptional repression in leukemic cells, involving complex functional connections between SPI1 and the epigenetic regulators PRC2 and HDAC1.


Asunto(s)
Histona Desacetilasa 1 , Leucemia Eritroblástica Aguda , Complejo Represivo Polycomb 2 , Proteínas Proto-Oncogénicas , Transactivadores , Acetilación , Animales , Cromatina/genética , Histona Desacetilasa 1/genética , Leucemia Eritroblástica Aguda/genética , Ratones , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/genética , Transactivadores/genética
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