MiRNAs confer phenotypic robustness to gene networks by suppressing biological noise.
miRNAs are small non-coding RNAs able to modulate target gene expression. It has been postulated that miRNAs confer robustness to biological processes, but clear experimental evidence is still missing. Here, using a synthetic biological approach, we demonstrate that microRNAs provide phenotypic robustness to transcriptional regulatory networks by buffering fluctuations in protein levels. We construct a network motif in mammalian cells exhibiting a 'toggle-switch' phenotype in which two alternative protein expression levels define its ON and OFF states. The motif consists of an inducible transcription factor that self-regulates its own transcription and that of a miRNA against the transcription factor itself. We confirm, using mathematical modelling and experimental approaches, that the microRNA confers robustness to the toggle-switch by enabling the cell to maintain and transmit its state. When absent, a dramatic increase in protein noise level occurs, causing the cell to randomly switch between the two states.
1] Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, 80131 Naples, Italy [2] Department of Biological Engineering, Massachusetts Institute of Technology. 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [3].
Velia
V
Siciliano
Immacolata
I
Garzilli
Chiara
C
Fracassi
Stefania
S
Criscuolo
Simona
S
Ventre
Diego
D
di Bernardo
D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D005822:Genetic Vectors; D016086:Lentivirus / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D010641:Phenotype; D014176:Protein Biosynthesis; D013269:Stochastic Processes; D058615:Synthetic Biology; D014158:Transcription, Genetic
D050687:E2F1 Transcription Factor; D035683:MicroRNAs