6 research outputs found
Quantitative analysis of competition in post-transcriptional regulation reveals a novel signature in target expression variation
When small RNAs are loaded onto Argonaute proteins they can form the
RNA-induced silencing complexes (RISCs), which mediate RNA interference.
RISC-formation is dependent on a shared pool of Argonaute proteins and RISC
loading factors, and is thus susceptible to competition among small RNAs for
loading. We present a mathematical model that aims to understand how small RNA
competition for the PTR resources affects target gene repression. We discuss
that small RNA activity is limited by RISC-formation, RISC-degradation and the
availability of Argonautes. Together, these observations explain a number of
PTR saturation effects encountered experimentally. We show that different
competition conditions for RISC-loading result in different signatures of PTR
activity determined also by the amount of RISC-recycling taking place. In
particular, we find that the small RNAs less efficient at RISC-formation, using
fewer resources of the PTR pathway, can perform in the low RISC-recycling range
equally well as their more effective counterparts. Additionally, we predict a
novel signature of PTR in target expression levels. Under conditions of low
RISC-loading efficiency and high RISC-recycling, the variation in target levels
increases linearly with the target transcription rate. Furthermore, we show
that RISC-recycling determines the effect that Argonaute scarcity conditions
have on target expression variation. Our observations taken together offer a
framework of predictions which can be used in order to infer from experimental
data the particular characteristics of underlying PTR activity.Comment: 23 pages, 3 Figures, accepted for publication to the Biophysical
Journa
Can we always sweep the details of RNA-processing under the carpet?
RNA molecules follow a succession of enzyme-mediated processing steps from
transcription until maturation. The participating enzymes, for example the
spliceosome for mRNAs and Drosha and Dicer for microRNAs, are also produced in
the cell and their copy-numbers fluctuate over time. Enzyme copy-number changes
affect the processing rate of the substrate molecules; high enzyme numbers
increase the processing probability, low enzyme numbers decrease it. We study
different RNA processing cascades where enzyme copy-numbers are either fixed or
fluctuate. We find that for fixed enzyme-copy numbers the substrates at
steady-state are Poisson-distributed, and the whole RNA cascade dynamics can be
understood as a single birth-death process of the mature RNA product. In this
case, solely fluctuations in the timing of RNA processing lead to variation in
the number of RNA molecules. However, we show analytically and numerically that
when enzyme copy-numbers fluctuate, the strength of RNA fluctuations increases
linearly with the RNA transcription rate. This linear effect becomes stronger
as the speed of enzyme dynamics decreases relative to the speed of RNA
dynamics. Interestingly, we find that under certain conditions, the RNA cascade
can reduce the strength of fluctuations in the expression level of the mature
RNA product. Finally, by investigating the effects of processing polymorphisms
we show that it is possible for the effects of transcriptional polymorphisms to
be enhanced, reduced, or even reversed. Our results provide a framework to
understand the dynamics of RNA processing
How epigenetic mutations can affect genetic evolution: Model and mechanism
We hypothesize that heritable epigenetic changes can affect rates of fitness increase as well as patterns of genotypic and phenotypic change during adaptation. In particular, we suggest that when natural selection acts on pure epigenetic variation in addition to genetic variation, populations adapt faster, and adaptive phenotypes can arise before any genetic changes. This may make it difficult to reconcile the timing of adaptive events detected using conventional population genetics tools based on DNA sequence data with environmental drivers of adaptation, such as changes in climate. Epigenetic modifications are frequently associated with somatic cell differentiation, but recently epigenetic changes have been found that can be transmitted over many generations. Here, we show how the interplay of these heritable epigenetic changes with genetic changes can affect adaptive evolution, and how epigenetic changes affect the signature of selection in the genetic record