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Robust Filtering and Noise Suppression in Intragenic miRNA-Mediated Host Regulation

Authors: 
Kang T, Quarton T, Nowak CM, Ehrhardt K, Singh A, Li Y, Bleris L
Citation: 
iScience. 2020 Sep 21;23(10):101595. doi: 10.1016/j.isci.2020.101595. eCollection 2020 Oct 23
Abstract: 
MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate gene expression post-transcriptionally by binding to target messenger RNAs (mRNAs). Many human miRNAs are intragenic, located within introns of protein-coding sequence (host). Intriguingly, a percentage of intragenic miRNAs downregulate the host transcript forming an incoherent feedforward motif topology. Here, we study intragenic miRNA-mediated host gene regulation using a synthetic gene circuit stably integrated within a safe-harbor locus of human cells. When the intragenic miRNA is directed to inhibit the host transcript, we observe a reduction in reporter expression accompanied by output filtering and noise reduction. Specifically, the system operates as a filter with respect to promoter strength, with the threshold being robust to promoter strength and measurement time. Additionally, the intragenic miRNA regulation reduces expression noise compared to splicing-alone architecture. Our results provide a new insight into miRNA-mediated gene expression, with direct implications to gene therapy and synthetic biology applications.
Epub: 
Not Epub
Organism or Cell Type: 
cell culture: HEK293