MicroRNA sensing and processing circuit in mammalian cells

MicroRNAs (miRNAs) are endogenous 21-23 nt RNAs that pair to mRNAs to exert posttranscriptional repression mainly in metazoans and plants. MicroRNAs play important roles in nearly every aspect of biology, including development and progression of cancers and a variety of other diseases. Although intensive studies have greatly improved our knowledge of the mechanisms of microRNA-mediated RNA interference, our understanding of how dynamics of multiple microRNA levels determine transitions of cellular states is still limited.

We design and create two types of microRNA sensors. Our microRNA high-sensor produces high output when microRNA input is high, while the low-sensor produces high output when microRNA input is low. We study the characteristics of microRNA high- and low-sensors, including sensitivity, response transfer function, and robustness, by developing mathematical models and testing sensors experimentally in mammalian cells. Applying these design principles, we are able to integrate both high-sensors and low-sensors to engineer complex circuits, triggering a predictable function in response to dynamic changes of multiple microRNA inputs. Hence, such a circuit will not only provide tools for studying microRNA dynamics during cell-state transition, but also enable programmable and precise manipulation of biological functions in specific cells.

People: Zhen Xie; Lila Wroblewska; Jeremy Gam