Stavreva Diana A, Garcia David A, Fettweis Gregory, Gudla Prabhakar R, Zaki George F, Soni Vikas, McGowan Andrew, Williams Geneva, Huynh Anh, Palangat Murali, Schiltz R Louis, Johnson Thomas A, Presman Diego M, Ferguson Matthew L, Pegoraro Gianluca, Upadhyaya Arpita, Hager Gordon L
Laboratory of Receptor Biology and Gene Expression, 41 Library Drive, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-5055, USA.
Laboratory of Receptor Biology and Gene Expression, 41 Library Drive, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-5055, USA; Department of Physics and Institute for Physical Science and Technology, University of Maryland, College Park, MD 20742, USA.
Mol Cell. 2019 Sep 19;75(6):1161-1177.e11. doi: 10.1016/j.molcel.2019.06.042. Epub 2019 Aug 14.
Genes are transcribed in a discontinuous pattern referred to as RNA bursting, but the mechanisms regulating this process are unclear. Although many physiological signals, including glucocorticoid hormones, are pulsatile, the effects of transient stimulation on bursting are unknown. Here we characterize RNA synthesis from single-copy glucocorticoid receptor (GR)-regulated transcription sites (TSs) under pulsed (ultradian) and constant hormone stimulation. In contrast to constant stimulation, pulsed stimulation induces restricted bursting centered around the hormonal pulse. Moreover, we demonstrate that transcription factor (TF) nuclear mobility determines burst duration, whereas its bound fraction determines burst frequency. Using 3D tracking of TSs, we directly correlate TF binding and RNA synthesis at a specific promoter. Finally, we uncover a striking co-bursting pattern between TSs located at proximal and distal positions in the nucleus. Together, our data reveal a dynamic interplay between TF mobility and RNA bursting that is responsive to stimuli strength, type, modality, and duration.
基因以一种称为RNA爆发的不连续模式进行转录，但调节这一过程的机制尚不清楚。尽管许多生理信号，包括糖皮质激素，都是脉动性的，但瞬时刺激对爆发的影响尚不清楚。在这里，我们描述了在脉冲（超日节律）和持续激素刺激下，单拷贝糖皮质激素受体（GR）调控的转录位点（TSs）的RNA合成情况。与持续刺激相反，脉冲刺激诱导以激素脉冲为中心的受限爆发。此外，我们证明转录因子（TF）的核迁移率决定爆发持续时间，而其结合分数决定爆发频率。通过对TSs进行三维跟踪，我们直接关联了特定启动子处的TF结合与RNA合成。最后，我们在细胞核近端和远端位置的TSs之间发现了一种显著的共爆发模式。总之，我们的数据揭示了TF迁移率与RNA爆发之间的动态相互作用，这种相互作用对刺激强度、类型、方式和持续时间有响应。
