RESUMEN
Accumulation of senescent cells during aging contributes to chronic inflammation and age-related diseases. While senescence is associated with profound alterations of the epigenome, a systematic view of epigenetic factors in regulating senescence is lacking. Here, we curated a library of short hairpin RNAs for targeted silencing of all known epigenetic proteins and performed a high-throughput screen to identify key candidates whose downregulation can delay replicative senescence of primary human cells. This screen identified multiple new players including the histone acetyltransferase p300 that was found to be a primary driver of the senescent phenotype. p300, but not the paralogous CBP, induces a dynamic hyper-acetylated chromatin state and promotes the formation of active enhancer elements in the non-coding genome, leading to a senescence-specific gene expression program. Our work illustrates a causal role of histone acetyltransferases and acetylation in senescence and suggests p300 as a potential therapeutic target for senescence and age-related diseases.
Asunto(s)
Proliferación Celular , Senescencia Celular , Ensamble y Desensamble de Cromatina , Cromatina/enzimología , Fibroblastos/enzimología , Histonas/metabolismo , Procesamiento Proteico-Postraduccional , Factores de Transcripción p300-CBP/metabolismo , Acetilación , Proliferación Celular/genética , Senescencia Celular/genética , Cromatina/genética , Ensamble y Desensamble de Cromatina/genética , Represión Epigenética , Células HEK293 , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Histonas/genética , Humanos , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Factores de Tiempo , Transcripción Genética , Factores de Transcripción p300-CBP/genéticaRESUMEN
People with decompensated cirrhosis are often prescribed a complex regimen of therapeutic and prophylactic medications. In other chronic diseases, polypharmacy increases the risk of medication misadventure and medication-related problems (MRPs), with associated increased morbidity, mortality, and health care costs. This study examined MRPs in a cohort of ambulatory patients with a history of decompensated cirrhosis who were enrolled in a randomized controlled trial of a pharmacist-led, patient-oriented medication education intervention and assessed the association between MRPs and patient outcomes. A total of 375 MRPs were identified among 57 intervention patients (median, 6.0; interquartile range, 3.5-8.0 per patient; maximum 17). Nonadherence (31.5%) and indication issues (29.1%) were the most prevalent MRP types. The risk of potential harm associated with MRPs was low in 18.9% of instances, medium in 33.1%, and high in 48.0%, as categorized by a clinician panel using a risk matrix tool. Patients had a greater incidence rate of high-risk MRPs if they had a higher Child-Pugh score (incidence rate ratio [IRR], 1.31; 95% confidence interval [CI], 1.09-1.56); greater comorbidity burden (IRR, 1.15; 95% CI, 1.02-1.29); and were taking more medications (IRR, 1.12; 95% CI, 1.04-1.22). A total of 221 MRPs (58.9%) were resolved following pharmacist intervention. A greater proportion of high-risk MRPs were resolved compared to those of low and medium risk (68.9% versus 49.7%; P < 0.001). During the 12-month follow-up period, intervention patients had a lower incidence rate of unplanned admissions compared to usual care (IRR, 0.52; 95% CI, 0.30-0.92). Conclusion: High-risk MRPs are prevalent among adults with decompensated cirrhosis. Pharmacist intervention facilitated identification and resolution of high-risk MRPs and was associated with reduced incidence rate of unplanned hospital admissions in this group.