title: Rethinking gene regulatory networks in light of alternative splicing, intrinsically disordered protein domains, and post-translational modifications.
abstract: Models for genetic regulation and cell fate specification characteristically assume that gene regulatory networks (GRNs) are essentially deterministic and exhibit multiple stable states specifying alternative, but pre-figured cell fates. Mounting evidence shows, however, that most eukaryotic precursor RNAs undergo alternative splicing (AS) and that the majority of transcription factors contain intrinsically disordered protein (IDP) domains whose functionalities are context dependent as well as subject to post-translational modification (PTM). Consequently, many transcription factors do not have fixed cis-acting regulatory targets, and developmental determination by GRNs alone is untenable. Modeling these phenomena requires a multi-scale approach to explain how GRNs operationally interact with the intra- and intercellular environments. Evidence shows that AS, IDP, and PTM complicate gene expression and act synergistically to facilitate and promote time- and cell-specific protein modifications involved in cell signaling and cell fate specification and thereby disrupt a strict deterministic GRN-phenotype mapping. The combined effects of AS, IDP, and PTM give proteomes physiological plasticity, adaptive responsiveness, and developmental versatility without inefficiently expanding genome size. They also help us understand how protein functionalities can undergo major evolutionary changes by buffering mutational consequences.
authors.affiliation: Plant Biology Section, School of Integrative Plant Science, Cornell University Ithaca, NY, USA.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Niklas
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College Station, TX, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bondos
authors.affiliation: Center for Computational Biology and Bioinformatics, School of Medicine, Indiana University Indianapolis, IN, USA.
authors.forename: A Keith
authors.initials: AK
authors.lastname: Dunker
authors.affiliation: Department of Cell Biology and Anatomy, New York Medical College Valhalla, NY, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Newman
keywords: cell fate specification; combinatorial transcription regulation; development; eukaryotes; evolution; gene regulatory networks; multi-stable dynamical systems; protein structure