title: Large-scale mapping of sequence-function relations in small regulatory RNAs reveals plasticity and modularity.
abstract: Two decades into the genomics era the question of mapping sequence to function has evolved from identifying functional elements to characterizing their quantitative properties including, in particular, their specificity and efficiency. Here, we use a large-scale approach to establish a quantitative map between the sequence of a bacterial regulatory RNA and its efficiency in modulating the expression of its targets. Our approach generalizes the sort-seq method, introduced recently to analyze promoter sequences, in order to accurately quantify the efficiency of a large library of sequence variants. We focus on two small RNAs (sRNAs) in E. coli, DsrA and RyhB, and their regulation of both repressed and activated targets. In addition to precisely identifying functional elements in the sRNAs, our data establish quantitative relationships between structural and energetic features of the sRNAs and their regulatory activity, and characterize a large set of direct and indirect interactions between nucleotides. A core of these interactions supports a model where specificity can be enhanced by a rigid molecular structure. Both sRNAs exhibit a modular design with limited cross-interactions, dividing the requirements for structural stability and target binding among modules.
authors.affiliation: Department of Physics and FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Peterman
authors.affiliation: Department of Physics and FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Anat
authors.initials: A
authors.lastname: Lavi-Itzkovitz
authors.affiliation: Department of Physics and FAS Center for Systems Biology, Harvard University, Cambridge, MA 02138, USA elevine@fas.harvard.edu.
authors.forename: Erel
authors.initials: E
authors.lastname: Levine
mesh_terms: D005434:Flow Cytometry; D008954:Models, Biological; D009154:Mutation; D009690:Nucleic Acid Conformation; D058727:RNA, Small Untranslated / Q000737:chemistry* / Q000378:metabolism; D017423:Sequence Analysis, RNA
chemical_list: C405431:DsrA RNA, E coli; D058727:RNA, Small Untranslated