Chromosomal origin of replication coordinates logically distinct types of bacterial genetic regulation

Kosmas Kosmidis,Georgi Muskhelishvili,Marc-Thorsten Hütt,Kim Philipp Jablonski

doi:10.1038/s41540-020-0124-1

Abstract

For a long time it has been hypothesized that bacterial gene regulation involves an intricate interplay of the transcriptional regulatory network (TRN) and the spatial organization of genes in the chromosome. Here we explore this hypothesis both on a structural and on a functional level. On the structural level, we study the TRN as a spatially embedded network. On the functional level, we analyze gene expression patterns from a network perspective (“digital control”), as well as from the perspective of the spatial organization of the chromosome (“analog control”). Our structural analysis reveals the outstanding relevance of the symmetry axis defined by the origin (Ori) and terminus (Ter) of replication for the network embedding and, thus, suggests the co-evolution of two regulatory infrastructures, namely the transcriptional regulatory network and the spatial arrangement of genes on the chromosome, to optimize the cross-talk between two fundamental biological processes: genomic expression and replication. This observation is confirmed by the functional analysis based on the differential gene expression patterns of more than 4000 pairs of microarray and RNA-Seq datasets for E. coli from the Colombos Database using complex network and machine learning methods. This large-scale analysis supports the notion that two logically distinct types of genetic control are cooperating to regulate gene expression in a complementary manner. Moreover, we find that the position of the gene relative to the Ori is a feature of very high predictive value for gene expression, indicating that the Ori–Ter symmetry axis coordinates the action of distinct genetic control mechanisms.

Highlights

In spite of the tremendous progress made in Systems Biology[1,2,3] and the construction of computational models of biological cells,[4,5] we still lack the appropriate understanding of the underlying principles of genetic regulation to predict, for example, the gene expression pattern of a bacterium
We explore the hypothesis that bacterial gene regulation is organized as an interplay of two distinct types of control—one exerted by the transcriptional regulatory network (TRN) (“digital control”) and one arising from the spatial organization of the chromosome (“analog control”)
We start by employing methods from statistical physics of complex networks, in order to identify the non-random features characterizing the chromosomal embedding of the transcriptional regulatory network

Summary

INTRODUCTION

In spite of the tremendous progress made in Systems Biology[1,2,3] and the construction of computational models of biological cells,[4,5] we still lack the appropriate understanding of the underlying principles of genetic regulation to predict, for example, the gene expression pattern of a bacterium. Since the beginning of Systems Biology, the investigation of bacterial gene regulation has been an important source of hypotheses about the principles of biological regulation.[6,7,8,9] The transcriptional regulatory network (TRN) of the classical model organism Escherichia coli has been the subject of a vast number of statistical analyses This network has been the first example of a complex network for which a non-random network motif distribution (deviations from randomness of the counts of small subgraphs) has been reported.[6,10] In spite of its prominence and the diversity of investigations, this network has been mostly studied in isolation. By analyzing (i) the distribution statistics of links in the transcriptional regulatory network, (ii) the agreement of gene expression patterns with both, the TRN and the distribution of genes in the genome, and (iii) the “learnability” of gene expression patterns by a decision tree employing various chromosomal and regulatory features we have been able to establish two main components of the logic underlying bacterial gene expression: (1) The Ori–Ter axis is a relevant organizer of gene expression; (2) Chromosomal structure (“analog control”) and transcription factors (“digital control”) contribute to regulation in an “either–or” fashion with one level of control buffering the other

RESULTS

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METHODS

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