August 31, 2022
Developing and maintaining life requires a lot of computation. This is done by gene regulatory networks. But we have little understanding of how this computation is organized. I show that there is a direct correspondence between the structural and functional building blocks of regulatory networks, which I call regulatory motifs. I derive a simple bound on the range of function that these motifs can perform, in terms of the local network structure. I prove that this range is a small fraction of all possible functions, which severely constrains global network behavior. Part of this restriction is due to redundancy in the function that regulatory motifs can achieve - there are many ways to perform the same task. Regulatory motifs help us understanding how genetic computation is organized and what it can achieve.
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September 26, 2021
Networks of gene regulation govern morphogenesis, determine cell identity and regulate cell function. But we have little understanding, at the local level, of which logics are biologically preferred or even permitted. To solve this puzzle, we studied the consequences of a fundamental aspect of gene regulatory networks: genes and transcription factors talk to each other but not themselves. Remarkably, this bipartite structure severely restricts the number of logical dependenci...
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The biological processes of cellular decision making and differentiation involve a plethora of signalling pathways and gene regulatory circuits. These networks, in their turn, exhibit a multitude of motifs playing crucial parts in regulating network activity. Here, we compare the topological placement of motifs in gene regulatory and signalling networks and find that it suggests different evolutionary strategies in motif distribution for distinct cellular subnetworks.
Gene regulatory networks arise in all living cells, allowing the control of gene expression patterns. The study of their topology has revealed that certain subgraphs of interactions or "motifs" appear at anomalously high frequencies. We ask here whether this phenomenon may emerge because of the functions carried out by these networks. Given a framework for describing regulatory interactions and dynamics, we consider in the space of all regulatory networks those that have a pr...
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Gene Regulatory Networks (GRNs) consisting of combinations of transcription factors (TFs) and their cis promoters are assumed to be sufficient to direct the development of organisms. Mutations in GRNs are assumed to be the primary drivers for the evolution of multicellular life. Here it is proven that neither of these assumptions is correct. They are inconsistent with fundamental principles of combinatorics of bounded encoded networks. It is shown there are inherent complexit...
Interaction networks are of central importance in post-genomic molecular biology, with increasing amounts of data becoming available by high-throughput methods. Examples are gene regulatory networks or protein interaction maps. The main challenge in the analysis of these data is to read off biological functions from the topology of the network. Topological motifs, i.e., patterns occurring repeatedly at different positions in the network have recently been identified as basic ...
Gene duplication is a fundamental evolutionary mechanism that contributes to biological complexity and diversity (Fortna et al., 2004). Traditionally, research has focused on the duplication of gene sequences (Zhang, 1914). However, evidence suggests that the duplication of regulatory elements may also play a significant role in the evolution of genomic functions (Teichmann and Babu, 2004; Hallin and Landry, 2019). In this work, the evolution of regulatory relationships belon...
Over the past decade, a number of researchers in systems biology have sought to relate the function of biological systems to their network-level descriptions -- lists of the most important players and the pairwise interactions between them. Both for large networks (in which statistical analysis is often framed in terms of the abundance of repeated small subgraphs) and for small networks which can be analyzed in greater detail (or even synthesized in vivo and subjected to expe...
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Biological and technological networks contain patterns, termed network motifs, which occur far more often than in randomized networks. Network motifs were suggested to be elementary building blocks that carry out key functions in the network. It is of interest to understand how network motifs combine to form larger structures. To address this, we present a systematic approach to define 'motif generalizations': families of motifs of different sizes that share a common architec...
Genetic regulatory networks enable cells to respond to the changes in internal and external conditions by dynamically coordinating their gene expression profiles. Our ability to make quantitative measurements in these biochemical circuits has deepened our understanding of what kinds of computations genetic regulatory networks can perform and with what reliability. These advances have motivated researchers to look for connections between the architecture and function of geneti...
Gene regulatory networks typically have low in-degrees, whereby any given gene is regulated by few of the genes in the network. What mechanisms might be responsible for these low in-degrees? Starting with an accepted framework of the binding of transcription factors to DNA, we consider a simple model of gene regulatory dynamics. In this model, we show that the constraint of having a given function leads to the emergence of minimum connectivities compatible with function. We e...