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Cell Syst. 2017 Dec 27;5(6):646-653.e5. doi: 10.1016/j.cels.2017.10.013. Epub 2017 Nov 15.

Asymmetry between Activation and Deactivation during a Transcriptional Pulse.

Author information

1
Division of Endocrinology, Diabetes and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, AV Hill Building, Manchester M13 9PT, UK.
2
Warwick Systems Biology Centre, University of Warwick, Coventry CV4, 7AL, UK.
3
Division of Cellular and Molecular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK.
4
Department of Statistics, University of Warwick, Coventry CV4 7AL, UK.
5
Department of Statistics, University of Warwick, Coventry CV4 7AL, UK. Electronic address: barbel.finkenstadt@warwick.ac.uk.
6
Division of Cellular and Molecular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, UK. Electronic address: mike.white@manchester.ac.uk.
7
Division of Endocrinology, Diabetes and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, AV Hill Building, Manchester M13 9PT, UK. Electronic address: julian.davis@manchester.ac.uk.

Abstract

Transcription in eukaryotic cells occurs in gene-specific bursts or pulses of activity. Recent studies identified a spectrum of transcriptionally active "on-states," interspersed with periods of inactivity, but these "off-states" and the process of transcriptional deactivation are poorly understood. To examine what occurs during deactivation, we investigate the dynamics of switching between variable rates. We measured live single-cell expression of luciferase reporters from human growth hormone or human prolactin promoters in a pituitary cell line. Subsequently, we applied a statistical variable-rate model of transcription, validated by single-molecule FISH, to estimate switching between transcriptional rates. Under the assumption that transcription can switch to any rate at any time, we found that transcriptional activation occurs predominantly as a single switch, whereas deactivation occurs with graded, stepwise decreases in transcription rate. Experimentally altering cAMP signalling with forskolin or chromatin remodelling with histone deacetylase inhibitor modifies the duration of defined transcriptional states. Our findings reveal transcriptional activation and deactivation as mechanistically independent, asymmetrical processes.

KEYWORDS:

gene transcription; growth hormone; modeling; pituitary; prolactin

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