title: Multiplex Eukaryotic Transcription (In)activation: Timing, Bursting and Cycling of a Ratchet Clock Mechanism.
abstract: Activation of eukaryotic transcription is an intricate process that relies on a multitude of regulatory proteins forming complexes on chromatin. Chromatin modifications appear to play a guiding role in protein-complex assembly on chromatin. Together, these processes give rise to stochastic, often bursting, transcriptional activity. Here we present a model of eukaryotic transcription that aims to integrate those mechanisms. We use stochastic and ordinary-differential-equation modeling frameworks to examine various possible mechanisms of gene regulation by multiple transcription factors. We find that the assembly of large transcription factor complexes on chromatin via equilibrium-binding mechanisms is highly inefficient and insensitive to concentration changes of single regulatory proteins. An alternative model that lacks these limitations is a cyclic ratchet mechanism. In this mechanism, small protein complexes assemble sequentially on the promoter. Chromatin modifications mark the completion of a protein complex assembly, and sensitize the local chromatin for the assembly of the next protein complex. In this manner, a strict order of protein complex assemblies is attained. Even though the individual assembly steps are highly stochastic in duration, a sequence of them gives rise to a remarkable precision of the transcription cycle duration. This mechanism explains how transcription activation cycles, lasting for tens of minutes, derive from regulatory proteins residing on chromatin for only tens of seconds. Transcriptional bursts are an inherent feature of such transcription activation cycles. Bursting transcription can cause individual cells to remain in synchrony transiently, offering an explanation of transcriptional cycling as observed in cell populations, both on promoter chromatin status and mRNA levels.
authors.affiliation: Molecular Cell Physiology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Katja N
authors.initials: KN
authors.lastname: Rybakova
authors.affiliation: Systems Bioinformatics, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Bruggeman
authors.affiliation: School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Tomaszewska
authors.affiliation: Molecular Cell Physiology, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Martijn J
authors.initials: MJ
authors.lastname: Moné
authors.affiliation: School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Carlberg
authors.affiliation: Molecular Cell Physiology, VU University Amsterdam, Amsterdam, The Netherlands; Manchester Centre for Integrative Systems Biology, University of Manchester, Manchester, United Kingdom; Synthetic Systems Biology, Netherlands Institute for Systems Biology, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Hans V
authors.initials: HV
authors.lastname: Westerhoff
mesh_terms: D001683:Biological Clocks / Q000235:genetics*; D003198:Computer Simulation; D008957:Models, Genetic; D015233:Models, Statistical; D012333:RNA, Messenger / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D014157:Transcription Factors