Orchestration of lincRNA-p21 and miR-155 in Modulating the Adaptive Dynamics of HIF-1α.

Hypoxia-inducible factor-1 (HIF-1) is the key regulator of cellular adaptive response to hypoxia. Accumulating evidence shows that HIF-1 induces some non-coding RNAs (ncRNAs) including lncRNAs and miRNAs to modulate its own activity, enclosing several feedback loops. How the two classes of ncRNAs are orchestrated in the HIF-1-dependent adaptive response to hypoxia is poorly understood. By selecting lincRNA-p21 and miR-155 as the representatives, we develop an integrated model of the HIF-1 network comprising interlinked positive and negative feedback loops to clarify the interplay between the two ncRNAs in the hypoxic response. By numerical simulations, we find that coordination of lincRNA-p21 and miR-155 shapes the adaptive dynamics of HIF-1α: lincRNA-p21 induction in the early phase stimulates the upregulation of HIF-1α via stabilizing it, while miR-155 induction in the late phase promotes the recovery of HIF-1α via enhancing the degradation of its mRNA. Moreover, HIF-1α-induced PHD2 plays an auxiliary role in the decline of HIF-1α. In addition, lincRNA-p21 and miR-155 modulate each other via regulating HIF-1α activity. Together, lincRNA-p21 and miR-155 coordinate in modulating HIF-1α dynamics, and our work may shed light on the role for ncRNAs in the cellular adaptation to hypoxia.