Transcriptional bursting is a major source of noise in gene expression. The telegraph model of gene expression, whereby transcription switches between on and off states, is the dominant model for bursting. Recently, it was shown that the telegraph model cannot explain a number of experimental observations from perturbation data. Here, we study an alternative model that is consistent with the data and which explicitly describes RNA polymerase recruitment and polymerase pause release, two steps necessary for messenger RNA (mRNA) production. We derive the exact steady-state distribution of mRNA numbers and an approximate steady-state distribution of protein numbers, which are given by generalized hypergeometric functions. The theory is used to calculate the relative sensitivity of the coefficient of variation of mRNA fluctuations for thousands of genes in mouse fibroblasts. This indicates that the size of fluctuations is mostly sensitive to the rate of burst initiation and the mRNA degradation rate. Furthermore, we show that 1) the time-dependent distribution of mRNA numbers is accurately approximated by a modified telegraph model with a Michaelis-Menten like dependence of the effective transcription rate on RNA polymerase abundance, and 2) the model predicts that if the polymerase recruitment rate is comparable or less than the pause release rate, then upon gene replication, the mean number of RNA per cell remains approximately constant. This gene dosage compensation property has been experimentally observed and cannot be explained by the telegraph model with constant rates.
Birds occupy a unique position in the evolution of cardiac design. Their hearts are capable of cardiac performance on par with, or exceeding that of mammals, and yet the structure of their cardiomyocytes resemble those of reptiles. It has been suggested that birds use intracellular Ca2+ stored within the sarcoplasmic reticulum (SR) to power contractile function but neither SR Ca2+ content nor the cross-talk between channels underlying Ca2+-induced Ca2+-release (CICR) have been studied in adult birds. Here we used voltage clamp to investigate the Ca2+ storage and refilling capacities of the SR and the degree of transsarcolemmal and intracellular Ca2+ channel interplay in freshly isolated atrial and ventricular myocytes from the heart of the Japanese quail (Coturnix japonica). A transsarcolemmal Ca2+ current was detectable both in quail atrial and ventricular myocytes and was mediated only by L-type Ca2+ channels. The peak density of ICa was larger in ventricular cells than in atrial and exceeded that reported for mammalian myocardium recorded under similar conditions. Steady-state SR Ca2+ content of quail myocardium was also larger than that reported for mammals and reached 750.6±128.2 µmol l−1 in atrial cells and 423.3±47.2 µmol l−1 in ventricular cells at 24⁰C. We observed SR-Ca2+-dependent inactivation of ICa in ventricular myocytes indicating cross-talk between sarcolemmal Ca2+ channels and ryanodine receptors in the SR. However, this phenomenon was not observed in atrial myocytes. Taken together, these findings help to explain the high efficiency avian myocyte excitation-contraction coupling with regard to their reptilian-like cellular ultrastructure.
Transcriptional bursting is a major source of noise in gene expression. Motivated by recent experiments, we study a model including slow burst initiation and termination, and fast RNA polymerase recruitment and pause release. We show that the time-dependent distribution of mRNA numbers is accurately approximated by a telegraph model with a Michaelis-Menten like dependence of the e↵ective transcription rate on polymerase abundance. We also show that gene dosage compensation, a common feature of mammalian gene expression, is an emergent property of our stochastic model.
Recent advances in fluorescence microscopy have made it possible to measure the fluctuations of nascent (actively transcribed) RNA. These closely reflect transcription kinetics, as opposed to conventional measurements of mature (cellular) RNA, whose kinetics is affected by additional processes downstream of transcription. Here, we formulate a stochastic model which describes promoter switching, initiation, elongation, premature detachment, pausing, and termination while being analytically tractable. We derive exact closed-form expressions for the mean and variance of nascent RNA fluctuations on gene segments, as well as of total nascent RNA on a gene. We also obtain exact expressions for the first two moments of mature RNA fluctuations and approximate distributions for total numbers of nascent and mature RNA. Our results, which are verified by stochastic simulation, uncover the explicit dependence of the statistics of both types of RNA on transcriptional parameters and potentially provide a means to estimate parameter values from experimental data.
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