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.
Highlights
Eukaryotic transcription depends on dozens of proteins, including transcription factors (TFs), chromatin remodellers and RNA polymerase II components [1,2,3,4,5,6,7]
In multicellular organisms transcription activity of a single gene is regulated by many different signals. This leads to multiple transcription factors binding to the same promoter
Complexes are assembled in a strict order and new histone modifications sensitize the chromatin for the formation of the complex. This leads to a cyclic, ordered series of irreversible events that is fast and can be tightly regulated—a cyclic ratchet mechanism; like a mechanical ‘clock’
Summary
Eukaryotic transcription depends on dozens of proteins, including transcription factors (TFs), chromatin remodellers and RNA polymerase II components [1,2,3,4,5,6,7]. It is frequently more complex than prokaryotic transcription [8]. Even though we refer by ‘transcription regulation’ only to regulation of the transcription process itself and not to the regulation of gene expression through transcription, the complexity of eukaryotic transcription regulation is immense. Conditionally-active genes can respond to multiple TFs that activate RNA polymerase II complex assembly and modify the chromatin state of the gene’s regulatory region [13]
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