RESUMEN
Sensors that detect dsRNA stimulate IFN responses as a defense against viral infection. IFN responses are also well documented in a variety of human autoimmune diseases, including relapsing-remitting multiple sclerosis (MS), in which increased IFN responses result from increased levels of double-stranded endogenous Alu RNAs. Mechanisms underlying increases in double-stranded Alu RNAs in MS are obscure. We find widespread loss of adenosine-to-inosine editing of Alu RNAs in MS. Unedited Alu RNAs are potent activators of both IFN and NF-κB responses via the dsRNA sensors, RIG-I, and TLR3. Minor editing of highly active Alu elements abrogates the ability to activate both transcriptional responses. Thus, adenosine-to-inosine editing may also represent an important defense against autoimmune diseases such as MS.
Asunto(s)
Elementos Alu/inmunología , Esclerosis Múltiple Recurrente-Remitente/genética , Edición de ARN/inmunología , ARN Bicatenario/inmunología , Activación Transcripcional/inmunología , Adenosina/genética , Elementos Alu/genética , Proteína 58 DEAD Box/metabolismo , Conjuntos de Datos como Asunto , Células HEK293 , Humanos , Inflamación/genética , Inflamación/inmunología , Inosina/genética , Interferones/metabolismo , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/inmunología , FN-kappa B/metabolismo , ARN Bicatenario/genética , ARN Bicatenario/metabolismo , RNA-Seq , Receptores Inmunológicos/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunología , Células THP-1 , Receptor Toll-Like 3/metabolismo , Secuenciación Completa del GenomaRESUMEN
As a class, 'BET' inhibitors disrupt binding of bromodomain and extra-terminal motif (BET) proteins, BRD2, BRD3, BRD4 and BRDT, to acetylated histones preventing recruitment of RNA polymerase 2 to enhancers and promoters, especially super-enhancers, to inhibit gene transcription. As such, BET inhibitors may be useful therapeutics for treatment of cancer and inflammatory disease. For example, the small molecule BET inhibitor, JQ1, selectively represses MYC, an important oncogene regulated by a super-enhancer. IFN-γ, a critical cytokine for both innate and adaptive immune responses, is also regulated by a super-enhancer. Here, we show that JQ1 represses IFN-γ expression in TH1 polarized PBMC cultures, CD4+ memory T cells, and NK cells. JQ1 treatment does not reduce activating chromatin marks at the IFNG locus, but displaces RNA polymerase II from the locus. Further, IFN-γ expression recovers in polarized TH1 cultures following removal of JQ1. Our results show that JQ1 abrogates IFN-γ expression, but repression is reversible. Thus, BET inhibitors may disrupt the normal functions of the innate and adaptive immune response.
