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Mol Cell. 2019 Sep 19;75(6):1161-1177.e11. doi: 10.1016/j.molcel.2019.06.042. Epub 2019 Aug 14.

Transcriptional Bursting and Co-bursting Regulation by Steroid Hormone Release Pattern and Transcription Factor Mobility.

Author information

1
Laboratory of Receptor Biology and Gene Expression, 41 Library Drive, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-5055, USA. Electronic address: stavrevd@mail.nih.gov.
2
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.
3
Laboratory of Receptor Biology and Gene Expression, 41 Library Drive, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-5055, USA.
4
High Performance Computing Group, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
5
Department of Physics and Graduate Program in Biomolecular Science, Boise State University, Boise, ID 83725, USA.
6
Department of Physics and Institute for Physical Science and Technology, University of Maryland, College Park, MD 20742, USA.
7
Laboratory of Receptor Biology and Gene Expression, 41 Library Drive, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892-5055, USA. Electronic address: hagerg@exchange.nih.gov.

Abstract

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.

KEYWORDS:

3D orbital tracking; RNA synthesis; bursting kinetics; circadian cycle; glucocorticoid receptor; high-throughput imaging; single cell; single molecule tracking; transcription dynamics; ultradian hormone stimulation

PMID:
31421980
PMCID:
PMC6754282
[Available on 2020-09-19]
DOI:
10.1016/j.molcel.2019.06.042

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