Systems analysis of Lrp family expansions in an extreme halophile

Abstract

Lineage-specific expansions of transcription factors (TF) play an important role in increasing the repertoire of regulatory programs for dealing with complex environmental change. Here, we have investigated how an expanded family of Leucine Responsive Protein (Lrp) --one of the most widespread families of TFs in prokaryotes-- equips an organism with strategies for adapting to a dynamically changing environment. We have used a systems approach to study the entire family of 8 Lrps in Halobacterium salinarum NRC-1 by (i) mapping genome-wide binding locations for each Lrp; (ii) discovering co-location of binding sites for multiple Lrps; (iii) identifying conditional activities of Lrps by analyzing a compendium of 1018 transcriptome measurements in diverse environments; (iv) correlating mRNA level changes of Lrps and their targets across different environments to discover conditional regulatory targets of each Lrp; and (v) analyzing global transcriptional consequences of Lrp deletions. By integrating all of these data, we have reconstructed a systems scale transcriptional regulatory network (TRN) that has provided mechanistic insights into how the expanded family of 8 Lrps encodes complex environment-dependent global coordination of disparate metabolic pathways. A surprising Lrp-mediated coordination of copper efflux and glutamate metabolism was validated by performing global metabolomic analysis on three Lrp deletion strains.