Transcriptional outcomes and kinetic patterning of gene expression in response to NF-κB activation [ChIA-PET]

Transcription factor NF-κB regulates cellular responses to environmental cues. For many stimuli NF-κB resides only transiently in the nucleus. Consequently, time-dependent transcriptional outputs are a fundamental feature of NF-κB activation. Here we identify mechanisms that direct kinetic patterns of NF-κB-dependent gene expression and transcriptional outcomes in response to a transient NF-κB-inducing stimulus in B cells. By combining RELA binding, RNA polymerase II (Pol II) recruitment, and perturbation of NF-κB activation, we demonstrate that kinetic differences amongst early- and late-activated RELA target genes can be understood based on chromatin configuration prior to cell activation and RELA-dependent priming, respectively. Additionally, we identified genes that were repressed by RELA activation and others that responded to RELA-activated transcription factors. Cumulatively, our studies define an NF-κB-responsive inducible gene cascade in activated B cells. kinetic patterning of direct and indirect NF-κB targets

转录因子NF-κB（Transcription factor NF-κB）可调控细胞对环境信号的应答反应。在多种刺激条件下，NF-κB仅短暂定位于细胞核中。因此，随时间动态变化的转录输出是NF-κB激活的核心特征。本研究鉴定了B细胞中，针对短暂性NF-κB诱导刺激，调控NF-κB依赖性基因表达动力学模式及转录结局的相关机制。通过整合RELA结合实验、RNA聚合酶II（RNA polymerase II，Pol II）招募实验以及NF-κB激活干扰实验，我们证实：早期激活与晚期激活的RELA靶基因之间的动力学差异，可分别通过细胞激活前的染色质构型以及RELA依赖性预致敏来阐释。此外，我们鉴定出受RELA激活抑制的基因，以及对RELA激活的转录因子产生应答的基因。综上，本研究明确了激活B细胞中受NF-κB调控的可诱导基因级联反应，以及直接与间接NF-κB靶标的动力学调控模式。