Robust Filtering and Noise Suppression in Intragenic miRNA-Mediated Host Regulation
Taek Kang,
Tyler Quarton,
Chance M. Nowak,
Kristina Ehrhardt,
Abhyudai Singh,
Yi Li,
Leonidas Bleris
Affiliations
Taek Kang
Bioengineering Department, University of Texas at Dallas, Richardson, TX 75080, USA; Center for Systems Biology, University of Texas at Dallas, Richardson, TX 75080, USA
Tyler Quarton
Bioengineering Department, University of Texas at Dallas, Richardson, TX 75080, USA; Center for Systems Biology, University of Texas at Dallas, Richardson, TX 75080, USA
Chance M. Nowak
Center for Systems Biology, University of Texas at Dallas, Richardson, TX 75080, USA; Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, USA
Kristina Ehrhardt
Bioengineering Department, University of Texas at Dallas, Richardson, TX 75080, USA; Center for Systems Biology, University of Texas at Dallas, Richardson, TX 75080, USA
Abhyudai Singh
Department of Electrical Engineering, University of Delaware, Newark, DE 19716, USA
Yi Li
Bioengineering Department, University of Texas at Dallas, Richardson, TX 75080, USA; Center for Systems Biology, University of Texas at Dallas, Richardson, TX 75080, USA
Leonidas Bleris
Bioengineering Department, University of Texas at Dallas, Richardson, TX 75080, USA; Center for Systems Biology, University of Texas at Dallas, Richardson, TX 75080, USA; Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, USA; Corresponding author
Summary: 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.
