Open AccessAsymmetric positive feedback loops reliably control biological responses
Author(s) -
Ratushny Alexander V,
Saleem Ramsey A,
Sitko Katherine,
Ramsey Stephen A,
Aitchison John D
Publication year - 2012
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.1038/msb.2012.10
Subject(s) - biology , myogenesis , myod , retinoid x receptor , downregulation and upregulation , transcription factor , microbiology and biotechnology , positive feedback , systems biology , schizosaccharomyces , genetics , saccharomyces cerevisiae , yeast , nuclear receptor , schizosaccharomyces pombe , gene , electrical engineering , engineering
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.