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Gene regulatory networks are often partitioned into different types of recurring network motifs. A feed-forward loop (FFL) is a common motif in which an upstream regulator is a protein, typically a transcription factor, that regulates the expression of the target protein in two ways - first, directly by regulating the mRNA levels of the target protein and second, indirectly via an intermediate molecule that in turn regulates the target protein level. Investigations on two variants of FFL - purely transcriptional FFL (tFFL) and sRNA-mediated FFL (smFFL) reveal several advantages of using such motifs. Here, we study a distinct sRNA-driven FFL (sFFL) that was discovered recently in Salmonella enterica: The distinction being the upstream regulator here is not a protein but an sRNA that translationally activates the target protein expression directly; and also indirectly via regulation of the transcriptional activator of the target protein. This variant, i.e. sFFL has not been subjected to rigorous analysis. We, therefore, set out to understand two aspects. First is a quantitative comparison of the regulatory response of sFFL with tFFL and smFFL using a differential equation framework. Since, the process of gene expression is inherently stochastic, the second objective is to find how noise in gene expression affects the functionality of the sFFL. We find that unlike for tFFL and smFFL, the response of sFFL is stronger and faster: the change in target protein concentration is rapid and depends critically on the initial concentration of sRNA. Further, our analysis based on generating function approach and stochastic simulations leads to a non-trivial prediction that an optimal noise filtration can be attained depending on the synthesis rate of the upstream sRNA and the degradation rate of the intermediate transcriptional activator. A comparison with a simpler process involving only translational activation by sRNA indicates that the design of sFFL is crucial for optimal noise filtration. These observations prompt us to conclude that sFFL has distinct advantages where the master regulator, sRNA, plays a critical role not only in driving a rapid and strong response, but also a reliable response that depends critically on its concentration.
This article was published in the following journal.
Name: Physical biology
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A family of recombinases initially identified in BACTERIA. They catalyze the ATP-driven exchange of DNA strands in GENETIC RECOMBINATION. The product of the reaction consists of a duplex and a displaced single-stranded loop, which has the shape of the letter D and is therefore called a D-loop structure.
A genomic region found in DROSOPHILA. The region contains genes encoding BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS that play a critical role in the regulation of pattern formation during EMBRYONIC DEVELOPMENT.
A basic helix-loop-helix transcription factor that plays a critical role in HEMATOPOIESIS and as a positive regulator in the differentiation of ERYTHROID CELLS. Chromosome translocations involving the TAL-1 gene are associated with T-CELL ACUTE LYMPHOCYTIC LEUKEMIA.
Copies of nucleic acid sequence that are arranged in opposing orientation. They may lie adjacent to each other (tandem) or be separated by some sequence that is not part of the repeat (hyphenated). They may be true palindromic repeats, i.e. read the same backwards as forward, or complementary which reads as the base complement in the opposite orientation. Complementary inverted repeats have the potential to form hairpin loop or stem-loop structures which results in cruciform structures (such as CRUCIFORM DNA) when the complementary inverted repeats occur in double stranded regions.
An antennapedia-like homeodomain transcription factor that regulates the expression of multiple genes in the INTESTINAL MUCOSA. It plays a critical role in many processes from early differentiation to maintenance of the intestinal epithelial lining of both the small and large intestine.
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