Biological systems use a variety of feedback and feedforward mechanisms to establish and maintain specific cellular programs. In a recent study published in Cell Research, Lin et al. add RNA editing to an S-nitrosylation-induced feedforward process, which, together with another recently reported paradigm of RNA editing-mediated feedback control, implicates a new role of RNA editing in fine-tuning biological outputs.

Feedback (both positive and negative) loops employ an output to enhance or suppress the input of a pathway, whereas feedforward controls leverage the output of a pathway to influence additional biological processes.¹ Both feedback and feedforward loops are key parts of regulatory biology, best exemplified by the highly intertwined regulatory networks in interferon signaling, where specific control mechanisms often involve the induction of activators/repressors of transcription or translation or post-translational modifications (PTMs) of various regulatory proteins.² RNA processing and regulatory RNAs (both long non-coding RNAs and microRNAs) have also been implicated in various feedback and feedforward controls.^3,4 However, there is no precedent for the involvement of RNA editing — adenosine-to-inosine (A-to-I) conversion within double-stranded RNA (dsRNA) catalyzed by Adenosine Deaminase Acting on RNA (ADAR) — in such regulation. This knowledge gap has now been filled by two recent studies.^5,6