Abstract
During eukaryotic transcription, RNA polymerase (RNAP) translocates along DNA molecules covered with nucleosomes and other DNA binding proteins. Though the interactions between a single nucleosome and RNAP are by now fairly well understood, this understanding has not been synthesized into a description of transcription on crowded genes, where multiple RNAP transcribe through nucleosomes while preserving the nucleosome coverage. We here take a deductive modeling approach to establish the consequences of RNAP–nucleosome interactions for transcription in crowded environments. We show that under physiologically crowded conditions, the interactions of RNAP with nucleosomes induce a strong kinetic attraction between RNAP molecules, causing them to self-organize into stable and moving pelotons. The peloton formation quantitatively explains the observed nucleosome and RNAP depletion close to the initiation site on heavily transcribed genes. Pelotons further translate into short-timescale transcriptional bursts at termination, resulting in burst characteristics consistent with instances of bursty transcription observed in vivo. To facilitate experimental testing of our proposed mechanism, we present several analytic relations that make testable quantitative predictions.
Highlights
On every scale, motility is a hallmark of life [8, 28]
The intracellular environment is crowded [23], and translocating enzymes often have to bypass large amounts of other proteins bound to their track [21]. This is true for the eukaryotic RNA polymerases, as over 80% of eukaryotic DNA is organized into nucleosomes [41] that consists of 147 base pairs of DNA wrapped tightly around an octameric core of histone proteins
In the Supplementary Material we further show that the typical size of a bulk peloton is proportional to∆/2, which can be seen to combine the strength of the interaction between motors and roadblocks with the range of the interaction (∆ is the maximum typical distance over which two motors dynamically interact through roadblock depletion)
Summary
Motility is a hallmark of life [8, 28]. On the smallest scales, directed motion through the densely packed interior of cells is crucial for biogenesis, morphogenesis, and the timely delivery of vital cargo to distant parts [27]. The intracellular environment is crowded [23], and translocating enzymes often have to bypass large amounts of other proteins bound to their track [21] This is true for the eukaryotic RNA polymerases, as over 80% of eukaryotic DNA is organized into nucleosomes [41] that consists of 147 base pairs (bps) of DNA wrapped tightly around an octameric core of histone proteins. Maintaining this dense nucleosome coverage is important since it organizes genomic DNA into compact, higher order structures that can fit within the limited space of the cell nucleus, but it creates a formidable barrier to transcription [68]. The local degree of nucleosome coverage correlates with gene-expression levels [10, 18, 29, 41, 60, 69] showing that transcription activity has important implications for nucleosome coverage and vice versa
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