Analysis of diverse regulatory networks in a hierarchical context shows consistent tendencies for collaboration in the middle levels

Abstract

Gene regulatory networks have been shown to share some common aspects with commonplace social governance structures. Thus, we can get some intuition into their organization by arranging them into well-known hierarchical layouts. These hierarchies, in turn, can be placed between the extremes of autocracies, with welldefined levels and clear chains of command, and democracies, without such defined levels and with more co-regulatory partnerships between regulators. In general, the presence of partnerships decreases the variation in information flow amongst nodes within a level, more evenly distributing stress. Here we study various regulatory networks (transcriptional, modification, and phosphorylation) for five diverse species, Escherichia coli to human. We specify three levels of regulators-top, middle, and bottom-which collectively govern the non-regulator targets lying in the lowest fourth level. We define quantities for nodes, levels, and entire networks that measure their degree of collaboration and autocratic vs. democratic character. We show individual regulators have a range of partnership tendencies: Some regulate their targets in combination with other regulators in local instantiations of democratic structure, whereas others regulate mostly in isolation, in more autocratic fashion. Overall, we show that in all networks studied the middle level has the highest collaborative propensity and coregulatory partnerships occur most frequently amongst midlevel regulators, an observation that has parallels in corporate settings where middle managers must interact most to ensure organizational effectiveness. There is, however, one notable difference between networks in different species: The amount of collaborative regulation and democratic character increases markedly with overall genomic complexity.coregulatory partnerships | hierarchy | middle managers | autocracy | democracy

Analysis of the hierarchical structure of the B. subtilis transcriptional regulatory network

“…The results discussed above are consistent with those of recent studies, which established that the global structure of TRNs in microorganisms can be characterized by a largely hierarchical structure 8,9,14,[17][18][19][20] with limited feedback in transcriptional regulation. We next quantified the extent of hierarchical organization in the TRNs of B. subtilis and E. coli and classified their genes into different levels of hierarchy.…”

“…Hence, we allowed the possibility of genes in SCC to be assigned to the Top, Middle and Bottom levels in contrast to Bhardwaj et al 20 .…”

“…It has thus been realised that there is a broad distribution 5,11,15 in the number of target genes directly regulated by a TF, and there are repeated occurrences of certain subgraphs, known as 'network motifs' 3,16 in TRNs. Several studies on the large-scale structure of TRNs, including in particular Escherichia coli and Saccharomyces cerevisiae, have established the existence of an inherent hierarchical architecture with limited feedback loops 8,9,14,[17][18][19][20] . The hierarchical structure of the TRN of E. coli has also been shown to enable cellular homeostasis and flexibility of responses to environmental changes 18 .…”

“…The hierarchical structure of the TRN of E. coli has also been shown to enable cellular homeostasis and flexibility of responses to environmental changes 18 . This architecture of TRNs allows the organization of transcriptional regulators and target genes into different levels 8,9,14,[17][18][19][20] . Investigations mainly in E. coli 8,9,17,18,20 and S. cerevisiae 9,19,20 have shown that genes in different hierarchical levels of TRNs have distinct structural, dynamical and evolutionary properties.…”

“…By analysing a series of recently proposed graph-theoretic measures 25 we quantified the extent of hierarchical organization in the TRNs of the two organisms studied here. Using well-established graph-theoretic algorithms 9,19,20 , we next classified transcriptional regulators into different hierarchical levels and studied the enrichment of various structural and functional properties in different levels of hierarchy in the two organisms. Our study reveals many unifying features, as well as some distinct ones, in the enrichment of structural and functional properties in different hierarchical levels of the TRNs of B. subtilis and E. coli.…”