RESUMEN
Super-enhancers (SEs) mediate high transcription levels of target genes. Previous studies have shown that SEs recruit transcription complexes and generate enhancer RNAs (eRNAs). We characterized transcription at the human and murine ß-globin locus control region (LCR) SE. We found that the human LCR is capable of recruiting transcription complexes independently from linked globin genes in transgenic mice. Furthermore, LCR hypersensitive site 2 (HS2) initiates the formation of bidirectional transcripts in transgenic mice and in the endogenous ß-globin gene locus in murine erythroleukemia (MEL) cells. HS2 3'eRNA is relatively unstable and remains in close proximity to the globin gene locus. Reducing the abundance of HS2 3'eRNA leads to a reduction in ß-globin gene transcription and compromises RNA polymerase II (Pol II) recruitment at the promoter. The Integrator complex has been shown to terminate eRNA transcription. We demonstrate that Integrator interacts downstream of LCR HS2. Inducible ablation of Integrator function in MEL or differentiating primary human CD34+ cells causes a decrease in expression of the adult ß-globin gene and accumulation of Pol II and eRNA at the LCR. The data suggest that transcription complexes are assembled at the LCR and transferred to the globin genes by mechanisms that involve Integrator mediated release of Pol II and eRNA from the LCR.
Asunto(s)
Elementos de Facilitación Genéticos , Regulación de la Expresión Génica , ARN/metabolismo , Transcripción Genética , Globinas beta/genética , Adulto , Animales , Línea Celular Tumoral , Endorribonucleasas/genética , Feto , Humanos , Hígado/embriología , Hígado/metabolismo , Región de Control de Posición , Ratones Transgénicos , ARN/fisiología , ARN Polimerasa II/metabolismo , Globinas beta/biosíntesisRESUMEN
Lyme disease (LD), or Lyme borreliosis, is a vector-borne disease that is caused by the transmission of the bacterium Borrelia burgdorferi through a tick bite. The symptoms of LD can persist in individuals chronically, even after the treatment and resolution of the initial infection. These symptoms include various neuropsychiatric manifestations and cognitive decline. The purpose of this review was to report the neuropsychiatric manifestations, cognitive decline, and effects of a delayed diagnosis on symptom severity in patients with long-standing LD (LSLD). A scoping review was conducted utilizing the electronic databases Embase, Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), and Web of Science. A total of 744 articles were retrieved and considered for inclusion. After a rigorous screening process, 10 articles that met the inclusion criteria for this review were included (i.e., reported neuropsychiatric manifestations and cognitive decline in patients with LSLD and the effects of a delayed diagnosis). Neuropsychiatric manifestations in the patients consisted of suicidal ideation, homicidal tendencies, extreme anger, depressive symptoms, aggression, and anxiety. Cognitive symptoms included dysfunctions in working memory, verbal learning/memory, non-verbal learning/memory, alertness, visuoconstructive, and frontal executive functioning. A delayed LD diagnosis increased symptom severity in most patients. The findings of this review indicate that neuropsychiatric and cognitive symptoms tend to present for a chronic period, even after disease recovery. Although researchers have established a link between a delayed LD diagnosis and increased symptom severity, LSLD is often an overlooked diagnosis in patients with neuropsychiatric symptoms and cognitive decline. More research is needed to compare the time to diagnosis and symptom severity in patients with LSLD.