Theoretical study of microRNA-mediated post-transcriptional regulation of gene expression noise

Adhikary, Raunak (2026) Theoretical study of microRNA-mediated post-transcriptional regulation of gene expression noise. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Raunak Adhikary (19RS093)) 19RS093.pdf - Submitted Version Restricted to Repository staff only Download (16MB)

Abstract

MicroRNAs (miRNAs) are key post-transcriptional regulators that shape gene expression variability through feedback motifs. Using mathematical modeling and simulations, we show how miRNA-mediated feedback controls both mean expression and noise in target mRNAs. Negative feedback introduces a threshold separating repressed and highly expressed states, with bimodal mRNA distributions emerging near this boundary. This bimodality, driven by anticorrelated fluctuations between miRNAs and mRNAs, is tuned by miRNA-mRNA binding affinity and feedback strength. Unlike direct auto-repression, miRNA regulation uniquely induces bimodality, thereby promoting phenotypic diversity. We further incorporate miRNA maturation, where precursor (pre-miRNA) and mature miRNAs compete for a shared pool of target mRNAs. This competition alters feedback dynamics: positive and negative feedback can act as bistable switches or oscillators, depending on relative degradation rates of pre- and mature miRNAs. Importantly, stochastic fluctuations generate bimodal mRNA distributions even outside the mean-field bifurcation regimes, highlighting that variability need not directly reflect deterministic dynamics. Overall, we provide mechanistic insights into how miRNA-based feedback enhances phenotypic diversity, with implications for development and disease.

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