Two by Two: Co-Regulating Adjacent Gene Pairs in Yeast and Beyond

Abstract

Ever since Jacob, Monod and their colleagues described how the multiple, tandemly arranged genes of the Lac operon from E. coli are co-regulated in response to different sugar substrates [1], one of the main pursuits of molecular biology has been to dissect the myriads of mechanisms whereby cells control and effect gene regulation. The importance of this question is evident across diverse areas of cellular and organismal biology, from the control of progression through the cell cycle in unicellular organisms, to the processes of development and differentiation in complex metazoans. Indeed, the 2012 Nobel Prize for Physiology or Medicine was recently awarded, in part, for research aimed at understanding and manipulating the regulatory circuits that can be used to reprogram the gene expression patterns of differentiated adult cells into those of so-called 'induced' pluripotent stem cells [2]. If anything, the significance of understanding how organisms 'use' their genes appropriately is as important as ever given that advancing, massively parallel DNA sequencing technologies continue to provide an ever-increasing catalog of new and diverse genomes.While there are many strategies that cells use to regulate the activities of their genes and gene products, one of the most critical strategies remains at the level of gene transcription. Our appreciation for how important and widespread this level of control is has increased immensely over the last decade, in part, because of the development of technologies such as micro-array analyses: a technique that allows for the quantitative assessment of mRNA levels under various conditions at a genome-wide scale [3]. So extensive has been this kind of analysis, that in some systems one can access genome-wide mRNA expression profiles from hundreds of different samples, conditions and time courses. The analysis of these datasets has allowed for the identification of groups of genes that share common regulatory responses to a given condition or stimulus, and subsequent analysis of their associated regulatory sequences has often revealed common promoter sequence motifs that represent targets for trans-acting regulatory factors [4]. In many ways, the control of these co-regulated gene sets, or regulons, has been found to echo the mechanism originally described for the control of the genes of the Lac operon. That is, mRNA expression levels are determined, in part, by the activities of transcription factors (i.e. the Lac repressor) that bind to promoter sequences (i.e. the Lac operator), thereby influencing the activity of RNA polymerase.Our own foray into this type of analysis began with the discovery that there was a large set of transcriptionally co-regulated genes in S. cerevisiae that contained a high proportion of members that were known to function in the ribosome and rRNA biogenesis (RRB) pathways [5]. As a group, the genes of the RRB regulon were transcriptionally repressed under stressful conditions (i.e. heat shock, nutrient deprivation etc.), and they were activated under c...