RESUMEN
Macrophages and myeloid dendritic cells (DCs) represent alternative differentiation options of bone marrow progenitors and blood monocytes. This choice profoundly influences the immune response under normal and pathological conditions, but the underlying transcriptional events remain unresolved. Here, we show that experimental activation of the transcription factors PU.1 and MafB in transformed chicken myeloid progenitors triggered alternative DC or macrophage fate, respectively. PU.1 activation also was instructive for DC fate in the absence of cytokines in human HL-60 cell-derived myeloid progenitor and monocyte clones. Differentiation of normal human monocytes to DCs led to a rapid increase of PU.1 to high levels that preceded phenotypic changes, but no MafB expression, whereas monocyte-derived macrophages expressed MafB and only moderate levels of PU.1. DCs inducing levels of PU.1 inhibited MafB expression in monocytes, which appeared to be required for DC specification, since constitutive MafB expression inhibited DC differentiation. Consistent with this, PU.1 directly bound to MafB, inhibited its transcriptional activity in macrophages, and repressed its ability to induce macrophage differentiation in chicken myeloid progenitors. We propose that high PU.1 activity favors DCs at the expense of macrophage fate by inhibiting expression and activity of the macrophage factor MafB.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Células Dendríticas/citología , Macrófagos/citología , Proteínas Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular/inmunología , Células Cultivadas , Embrión de Pollo , Pollos , Proteínas de Unión al ADN/genética , Células Dendríticas/fisiología , Regulación hacia Abajo/inmunología , Células Precursoras de Granulocitos/citología , Células Precursoras de Granulocitos/fisiología , Células HL-60 , Humanos , Macrófagos/fisiología , Factor de Transcripción MafB , Monocitos/citología , Monocitos/fisiología , Proteínas Oncogénicas/genética , Fenotipo , Proteínas Proto-Oncogénicas/genética , Transactivadores/genética , Factores de Transcripción/genética , Transcripción Genética/inmunología , Transformación GenéticaRESUMEN
Most transcriptional repression pathways depend on the targeted deacetylation of histone tails. In this report, we characterize NIR, a novel transcriptional corepressor with inhibitor of histone acetyltransferase (INHAT) activity. NIR (Novel INHAT Repressor) is ubiquitously expressed throughout embryonic development and adulthood. NIR is a potent transcriptional corepressor that is not blocked by histone deacetylase inhibitors and is capable of silencing both basal and activator-driven transcription. NIR directly binds to nucleosomes and core histones and prevents acetylation by histone acetyltransferases, thus acting as a bona fide INHAT. Using a tandem affinity purification approach, we identified the tumor suppressor p53 as a NIR-interacting partner. Association of p53 and NIR was verified in vitro and in vivo. Upon recruitment by p53, NIR represses transcription of both p53-dependent reporters and endogenous target genes. Knock-down of NIR by RNA interference significantly enhances histone acetylation at p53-regulated promoters. Moreover, p53-dependent apoptosis is robustly increased upon depletion of NIR. In summary, our findings describe NIR as a novel INHAT that plays an important role in the control of p53 function.