miRNAs confer phenotypic robustness to gene networks: a synthetic biology approach

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Immacolata Garzilli, Chiara Fracassi , Simona Ventre, Stefania Criscuolo, Diego di Bernardo

Telethon Institute of Genetics and Medicine (TIGEM), Italy

miRNAs are small non-coding RNAs able to modulate target-gene expression. It has been postulated that miRNAs may confer robustness to biological processes, but no clear evidence has been reported yet. Using a synthetic biology approach, we demonstrated that microRNAs provide phenotypic robustness to transcriptional regulatory networks by buffering fluctuations in protein levels. We constructed a network motif in mammalian cells, which is commonly found in endogenous regulatory networks, consisting of an inducible transcription factor that self-regulates its own transcription, and the transcription of a miRNA inhibiting the transcription factor itself. We confirmed, using mathematical modeling and experimental approaches, that this motif behaves as a “toggle-switch” in which two alternative protein expression levels define its ON and OFF states. The microRNA confers robustness to the toggle-switch, allowing the cell to maintain and transmit its state indefinitely. When absent,a dramatic increase in protein noise level occurs, causing the cell to randomly switch between the two states.