RESUMO
BRD4 governs pathological cardiac gene expression by binding acetylated chromatin, resulting in enhanced RNA polymerase II (Pol II) phosphorylation and transcription elongation. Here, we describe a signal-dependent mechanism for the regulation of BRD4 in cardiomyocytes. BRD4 expression is suppressed by microRNA-9 (miR-9), which targets the 3' UTR of the Brd4 transcript. In response to stress stimuli, miR-9 is downregulated, leading to derepression of BRD4 and enrichment of BRD4 at long-range super-enhancers (SEs) associated with pathological cardiac genes. A miR-9 mimic represses stimulus-dependent targeting of BRD4 to SEs and blunts Pol II phosphorylation at proximal transcription start sites, without affecting BRD4 binding to SEs that control constitutively expressed cardiac genes. These findings suggest that dynamic enrichment of BRD4 at SEs genome-wide serves a crucial role in the control of stress-induced cardiac gene expression and define a miR-dependent signaling mechanism for the regulation of chromatin state and Pol II phosphorylation.
Assuntos
MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Regiões 3' não Traduzidas/genética , Acetilação , Animais , Proteínas de Ciclo Celular , Cromatina/metabolismo , Regulação para Baixo/fisiologia , Humanos , Camundongos , Fosforilação/fisiologia , RNA Polimerase II/metabolismo , Ratos , Transdução de Sinais/fisiologia , Elongação da Transcrição Genética/fisiologia , Sítio de Iniciação de Transcrição/fisiologiaRESUMO
Regenerative medicine holds great potential to address many shortcomings in current medical therapies. An emerging avenue of regenerative medicine is the use of self-assembling peptides (SAP) in conjunction with stem cells to improve the repair of damaged tissues. The specific peptide sequence, mechanical properties, and nanotopographical cues vary widely between different SAPs, many of which have been used for the regeneration of similar tissues. To evaluate the potential of SAPs to guide stem cell fate, we extensively reviewed the literature for reports of SAPs and stem cell differentiation. To portray the most accurate summary of these studies, we deliberately discuss both the successes and pitfalls, allowing us to make conclusions that span the breadth of this exciting field. We also expand on these conclusions by relating these findings to the fields of nanotopography, mechanotransduction, and the native composition of the extracellular matrix in specific tissues to identify potential directions for future research.
