RESUMEN
Post-transcriptional mechanisms have the potential to influence complex changes in gene expression, yet their role in cell fate transitions remains largely unexplored. Here, we show that suppression of the RNA helicase DDX6 endows human and mouse primed embryonic stem cells (ESCs) with a differentiation-resistant, "hyper-pluripotent" state, which readily reprograms to a naive state resembling the preimplantation embryo. We further demonstrate that DDX6 plays a key role in adult progenitors where it controls the balance between self-renewal and differentiation in a context-dependent manner. Mechanistically, DDX6 mediates the translational suppression of target mRNAs in P-bodies. Upon loss of DDX6 activity, P-bodies dissolve and release mRNAs encoding fate-instructive transcription and chromatin factors that re-enter the ribosome pool. Increased translation of these targets impacts cell fate by rewiring the enhancer, heterochromatin, and DNA methylation landscapes of undifferentiated cell types. Collectively, our data establish a link between P-body homeostasis, chromatin organization, and stem cell potency.
Asunto(s)
Diferenciación Celular/genética , Plasticidad de la Célula/genética , ARN Helicasas DEAD-box/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Ribonucleoproteínas/metabolismo , Animales , Línea Celular , Ensamble y Desensamble de Cromatina/genética , ARN Helicasas DEAD-box/genética , Metilación de ADN , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Regulación de la Expresión Génica/genética , Ontología de Genes , Homeostasis/genética , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/enzimología , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteína Homeótica Nanog/metabolismo , Organoides/citología , Organoides/diagnóstico por imagen , Organoides/metabolismo , Biosíntesis de Proteínas/genética , Proteínas/metabolismo , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/metabolismo , RNA-Seq , Ribonucleoproteínas/genética , Ribosomas/metabolismoRESUMEN
Hypothetically, antibodies may neutralize enveloped viruses by diverse mechanisms, such as disruption of receptor binding, interference with conformational changes required for virus entry, steric hindrance, or virus aggregation. Here, we demonstrate that retroviral infection mediated by the avian sarcoma-leukosis virus (ASLV-A) envelope glycoproteins can be neutralized by an antibody directed against a functionally unimportant component of a chimeric receptor protein. Thus, the binding of an antibody in proximity to the retroviral envelope glycoprotein-receptor complex, without binding to the entry machinery itself, results in neutralization. This finding provides additional support for the hypothesis that steric hindrance is sufficient for antibody-mediated neutralization of retroviruses.