TitleAsymmetric positive feedback loops reliably control biological responses.
Publication TypeJournal Article
Year of Publication2012
AuthorsRatushny, AV, Saleem, RA, Sitko, K, Ramsey, SA, Aitchison, JD
JournalMol Syst Biol
Date Published2012 Apr 24
KeywordsFeedback, Physiological, Flow Cytometry, Gene Expression Regulation, Fungal, Gene Regulatory Networks, Models, Molecular, Saccharomyces cerevisiae, Signal Transduction, Systems Biology, Up-Regulation

Positive feedback is a common mechanism enabling biological systems to respond to stimuli in a switch-like manner. Such systems are often characterized by the requisite formation of a heterodimer where only one of the pair is subject to feedback. This ASymmetric Self-UpREgulation (ASSURE) motif is central to many biological systems, including cholesterol homeostasis (LXRα/RXRα), adipocyte differentiation (PPARγ/RXRα), development and differentiation (RAR/RXR), myogenesis (MyoD/E12) and cellular antiviral defense (IRF3/IRF7). To understand why this motif is so prevalent, we examined its properties in an evolutionarily conserved transcriptional regulatory network in yeast (Oaf1p/Pip2p). We demonstrate that the asymmetry in positive feedback confers a competitive advantage and allows the system to robustly increase its responsiveness while precisely tuning the response to a consistent level in the presence of varying stimuli. This study reveals evolutionary advantages for the ASSURE motif, and mechanisms for control, that are relevant to pharmacologic intervention and synthetic biology applications.

Alternate JournalMol Syst Biol
PubMed ID22531117
PubMed Central IDPMC3361002
Grant ListP50-GM076547 / GM / NIGMS NIH HHS / United States
U54 RR022220 / RR / NCRR NIH HHS / United States
P50 GM076547 / GM / NIGMS NIH HHS / United States
U54-2U54RR022220 / RR / NCRR NIH HHS / United States
R01 GM075152 / GM / NIGMS NIH HHS / United States
R01-GM075152 / GM / NIGMS NIH HHS / United States
K25 HL098807 / HL / NHLBI NIH HHS / United States