Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
Cell Rep. 2020 Jun 2;31(9):107724. doi: 10.1016/j.celrep.2020.107724.
NF-κB is a transcription factor that activates super enhancers (SEs) and typical enhancers (TEs) and triggers threshold and graded gene expression, respectively. However, the mechanisms by which NF-κB selectively participates in these enhancers remain unclear. Here we show using mouse primary B lymphocytes that SE activity simultaneously associates with chromatin opening and enriched NF-κB binding, resulting in a higher fold change and threshold expression upon B cell receptor (BCR) activation. The higher fold change results from longer DNA, whereas the threshold response is explained by synergy in DNA-NF-κB binding and is supported by the coexistence of PU.1 and NF-κB in a SE before cell stimulation. This model indicates that the pre-existing NF-κB functions as a seed and triggers its processive binding upon BCR activation. Our mathematical modeling of the single-cell transcriptome reveals an additional role for SEs in divergent clonal responses in B cells.
NF-κB 是一种转录因子，它分别激活超级增强子 (SEs) 和典型增强子 (TEs)，并触发阈值和分级基因表达。然而，NF-κB 选择性参与这些增强子的机制尚不清楚。在这里，我们使用小鼠原代 B 淋巴细胞表明，SE 活性同时与染色质开放和富含 NF-κB 结合相关联，导致 B 细胞受体 (BCR) 激活时更高的倍数变化和阈值表达。更高的倍数变化是由于更长的 DNA，而阈值反应则可以通过 DNA-NF-κB 结合的协同作用来解释，并得到细胞刺激前 SE 中 PU.1 和 NF-κB 共存的支持。该模型表明，预先存在的 NF-κB 作为种子起作用，并在 BCR 激活时触发其连续结合。我们对单细胞转录组的数学建模揭示了 SEs 在 B 细胞中发散克隆反应中的另一个作用。
