The influence of RNA kinetic rates on RNA abundance and responsiveness. (A) Schematic representation of the RNA life cycle, governed by the kinetics rates of synthesis, processing and degradation. (B) Deterministic mathematical model of the RNA life cycle based on Ordinary Differential Equations (ODEs), including the solution of the system at steady state. (C-L) Solution of the ODE system following the modulation of the kinetic rates: each example reports, for premature and mature RNA species (left) and for the kinetic rates (right), the ratio to the initial time point. Initial values are indicated within each panel.

The influence of RNA kinetic rates on RNA abundance and responsiveness. (A) Schematic representation of the RNA life cycle, governed by the kinetics rates of synthesis, processing and degradation. (B) Deterministic mathematical model of the RNA life cycle based on Ordinary Differential Equations (ODEs), including the solution of the system at steady state. (C-L) Solution of the ODE system following the modulation of the kinetic rates: each example reports, for premature and mature RNA species (left) and for the kinetic rates (right), the ratio to the initial time point. Initial values are indicated within each panel.

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The kinetic rates of RNA synthesis, processing and degradation determine the dynamics of transcriptional regulation by governing both the abundance and the responsiveness to modulations of premature and mature RNA species. The study of RNA dynamics is largely based on the integrative analysis of total and nascent transcription, with the latter bein...

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... failed to consider that the abundance of premature and mature RNA depends on the RNA life-cycle, whose three main steps are: premature RNA synthesis, processing of premature into mature RNA, and degradation of the latter 2 . These steps are governed by corresponding kinetic rates, which collectively determine the RNA dynamics of transcripts ( Fig. 1A). At steady-state, the abundance of each premature RNA is equal to the ratio of its synthesis to processing rate, and the quantity of its mature form is given by its synthesis to degradation rate ratio (Fig. 1B). Thus, while the rate of RNA synthesis influences the abundance of both premature and mature RNAs, processing and degradation ...
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... of the latter 2 . These steps are governed by corresponding kinetic rates, which collectively determine the RNA dynamics of transcripts ( Fig. 1A). At steady-state, the abundance of each premature RNA is equal to the ratio of its synthesis to processing rate, and the quantity of its mature form is given by its synthesis to degradation rate ratio (Fig. 1B). Thus, while the rate of RNA synthesis influences the abundance of both premature and mature RNAs, processing and degradation rates impact just on premature and mature forms, respectively. At the transition between steady-states, RNA kinetic rates define the speed at which the mature form of a transcript can be brought to a new level ...
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... copyright holder for this preprint . http://dx.doi.org/10.1101/520155 doi: bioRxiv preprint first posted online Jan. 14, 2019; where P and M abundances are calculated as k 1 /k 2 and k 1 /k 3 ratios, respectively (Fig. 1B,C); modulations in the processing rate k 2 cause just transient variations in M abundance but permanent alterations of P abundance (Fig. 1D); M responsiveness to k 1 adjustments depends on the level of k 3 (compare Fig. 1E and F) and can be reduced by decreasing k 2 (Fig. 1G); k 1 and k 3 can separately generate the same type of M ...
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... holder for this preprint . http://dx.doi.org/10.1101/520155 doi: bioRxiv preprint first posted online Jan. 14, 2019; where P and M abundances are calculated as k 1 /k 2 and k 1 /k 3 ratios, respectively (Fig. 1B,C); modulations in the processing rate k 2 cause just transient variations in M abundance but permanent alterations of P abundance (Fig. 1D); M responsiveness to k 1 adjustments depends on the level of k 3 (compare Fig. 1E and F) and can be reduced by decreasing k 2 (Fig. 1G); k 1 and k 3 can separately generate the same type of M variation if changing in opposite directions (Fig. 1F,H), while adjustments in k 1 only are able to effect P abundance (Fig. 1F); k 1 and k 3 ...
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... first posted online Jan. 14, 2019; where P and M abundances are calculated as k 1 /k 2 and k 1 /k 3 ratios, respectively (Fig. 1B,C); modulations in the processing rate k 2 cause just transient variations in M abundance but permanent alterations of P abundance (Fig. 1D); M responsiveness to k 1 adjustments depends on the level of k 3 (compare Fig. 1E and F) and can be reduced by decreasing k 2 (Fig. 1G); k 1 and k 3 can separately generate the same type of M variation if changing in opposite directions (Fig. 1F,H), while adjustments in k 1 only are able to effect P abundance (Fig. 1F); k 1 and k 3 reinforce each other's modulation of M (compare Fig. 1E with I) when they ...
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... abundances are calculated as k 1 /k 2 and k 1 /k 3 ratios, respectively (Fig. 1B,C); modulations in the processing rate k 2 cause just transient variations in M abundance but permanent alterations of P abundance (Fig. 1D); M responsiveness to k 1 adjustments depends on the level of k 3 (compare Fig. 1E and F) and can be reduced by decreasing k 2 (Fig. 1G); k 1 and k 3 can separately generate the same type of M variation if changing in opposite directions (Fig. 1F,H), while adjustments in k 1 only are able to effect P abundance (Fig. 1F); k 1 and k 3 reinforce each other's modulation of M (compare Fig. 1E with I) when they simultaneously change in opposite directions, but generate just a ...
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... rate k 2 cause just transient variations in M abundance but permanent alterations of P abundance (Fig. 1D); M responsiveness to k 1 adjustments depends on the level of k 3 (compare Fig. 1E and F) and can be reduced by decreasing k 2 (Fig. 1G); k 1 and k 3 can separately generate the same type of M variation if changing in opposite directions (Fig. 1F,H), while adjustments in k 1 only are able to effect P abundance (Fig. 1F); k 1 and k 3 reinforce each other's modulation of M (compare Fig. 1E with I) when they simultaneously change in opposite directions, but generate just a modulation of P if they are simultaneously adjusted in the same direction (Fig. 1J); a transient alteration of M ...
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... alterations of P abundance (Fig. 1D); M responsiveness to k 1 adjustments depends on the level of k 3 (compare Fig. 1E and F) and can be reduced by decreasing k 2 (Fig. 1G); k 1 and k 3 can separately generate the same type of M variation if changing in opposite directions (Fig. 1F,H), while adjustments in k 1 only are able to effect P abundance (Fig. 1F); k 1 and k 3 reinforce each other's modulation of M (compare Fig. 1E with I) when they simultaneously change in opposite directions, but generate just a modulation of P if they are simultaneously adjusted in the same direction (Fig. 1J); a transient alteration of M that has been induced by a temporary change in k 1 (Fig. 1K) can be ...
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... depends on the level of k 3 (compare Fig. 1E and F) and can be reduced by decreasing k 2 (Fig. 1G); k 1 and k 3 can separately generate the same type of M variation if changing in opposite directions (Fig. 1F,H), while adjustments in k 1 only are able to effect P abundance (Fig. 1F); k 1 and k 3 reinforce each other's modulation of M (compare Fig. 1E with I) when they simultaneously change in opposite directions, but generate just a modulation of P if they are simultaneously adjusted in the same direction (Fig. 1J); a transient alteration of M that has been induced by a temporary change in k 1 (Fig. 1K) can be made sharper by a concomitant change in k 3 (Fig. 1L, as discussed in 6 ...
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... if changing in opposite directions (Fig. 1F,H), while adjustments in k 1 only are able to effect P abundance (Fig. 1F); k 1 and k 3 reinforce each other's modulation of M (compare Fig. 1E with I) when they simultaneously change in opposite directions, but generate just a modulation of P if they are simultaneously adjusted in the same direction (Fig. 1J); a transient alteration of M that has been induced by a temporary change in k 1 (Fig. 1K) can be made sharper by a concomitant change in k 3 (Fig. 1L, as discussed in 6 ...
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... to effect P abundance (Fig. 1F); k 1 and k 3 reinforce each other's modulation of M (compare Fig. 1E with I) when they simultaneously change in opposite directions, but generate just a modulation of P if they are simultaneously adjusted in the same direction (Fig. 1J); a transient alteration of M that has been induced by a temporary change in k 1 (Fig. 1K) can be made sharper by a concomitant change in k 3 (Fig. 1L, as discussed in 6 ...
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... modulation of M (compare Fig. 1E with I) when they simultaneously change in opposite directions, but generate just a modulation of P if they are simultaneously adjusted in the same direction (Fig. 1J); a transient alteration of M that has been induced by a temporary change in k 1 (Fig. 1K) can be made sharper by a concomitant change in k 3 (Fig. 1L, as discussed in 6 ...
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... copyright holder for this preprint . http://dx.doi.org/10.1101/520155 doi: bioRxiv preprint first posted online Jan. 14, 2019; each kinetic rate in two alternative analytical forms (constant or impulsive) were considered. Each model was plugged within a system of ordinary differential equations (Fig. 1B). Optimization of the free parameters associated with the rates' functional forms was performed to minimize the error in the fit of the premature and mature RNAs time-course profiles. Finally, a model was selected that gave the best trade-off between complexity and goodness of fit. As a faster alternative, we developed a derivative ...
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... a model was selected that gave the best trade-off between complexity and goodness of fit. As a faster alternative, we developed a derivative approach based on an analytical solution of the system, allowing the deconvolution of gene-specific RNA dynamics in 20s per core, while minimally compromising on the quality of the results ( Supplementary Fig. 1). ...
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... and mature RNA abundances as well as their variations. RNA-dynamics from steady-state total RNA-seq data At steady-state and in the absence of nascent RNA profiling, no information is available on the rate of synthesis. However, the ratio of premature to mature RNA abundance is equal to the ratio of processing to degradation rate (k 2 /k 3 , Fig. 1B). While this ratio does not allow deconvoluting the individual contributions of the two rates, its change over different conditions indicates alterations in post-transcriptional regulation. ...
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... for each type of tissue, we analysed the functions of the genes with the higher values of í µí¼ and í µí»¥. This analysis surprisingly revealed a strong enrichment in genes associated with RNA metabolism and processing (FDR < 0.001, Supplementary Fig. 10). Thus, spliceosome genes seemed particularly sensitive to possibly subtle alterations in their processing kinetics, suggesting a feedback control for this important machinery. ...
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... doi: bioRxiv preprint first posted online Jan. 14, 2019; seq libraries prepared with various protocols including the poly-A selection step, are also suitable for these analyses (Supplementary Fig. 11; 40 ), thus broadening the scope of our approaches. ...

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