Genomic analysis reveals a tight link between transcription factor dynamics and regulatory network architecture

Abstract

Although several studies have provided important insights into the general principles of biological networks, the link between network organization and the genome-scale dynamics of the underlying entities (genes, mRNAs, and proteins) and its role in systems behavior remain unclear. Here we show that transcription factor (TF) dynamics and regulatory network organization are tightly linked. By classifying TFs in the yeast regulatory network into three hierarchical layers (top, core, and bottom) and integrating diverse genome-scale datasets, we find that the TFs have static and dynamic properties that are similar within a layer and different across layers. At the protein level, the top-layer TFs are relatively abundant, long-lived, and noisy compared with the core-and bottomlayer TFs. Although variability in expression of top-layer TFs might confer a selective advantage, as this permits at least some members in a clonal cell population to initiate a response to changing conditions, tight regulation of the core-and bottom-layer TFs may minimize noise propagation and ensure fidelity in regulation. We propose that the interplay between network organization and TF dynamics could permit differential utilization of the same underlying network by distinct members of a clonal cell population.

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

“…Using a vertex-sort algorithm 19 we determined the number of levels in the Top-down and Bottomup hierarchical decomposition of the TRNs of B. subtilis and E. coli (see Methods). The number of levels was found to be smaller than that observed in randomized networks (Table S1).…”

“…Leaf-removal procedure within the vertex-sort algorithm 19,42 can be used to decompose nodes into different levels in two different ways: Top-down and Bottom-up hierarchy. We determined the number of actual levels in both the Top-down and Bottom-up hierarchal decompositions of the TRNs of B. subtilis and E. coli (Table S1).…”

“…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.…”

SND1 Transcription Factor-Directed Quantitative Functional Hierarchical Genetic Regulatory Network in Wood Formation in Populus trichocarpa

“…Growth and development in multicellular organisms are regulated at many levels by transacting molecules following well-structured regulatory hierarchies (Riechmann et al, 2000;Davidson, 2001;Wray et al, 2003;Jothi et al, 2009). Understanding the regulatory hierarchy of wood formation will offer novel and more precise genetic approaches to improve the productivity of forest trees.…”

Rapid reorganization of the transcriptional regulatory network after genome duplication in yeast

“…Luscombe et al (2004) have shown that gene regulation in response to exogenous stimuli tends to involve fewer TFs per target and shorter regulatory cascades than do endogenous regulatory controls (such as the cell cycle). Additionally, Jothi et al (2009) found that differences in TF half-life were associated with a TF's position in the hierarchically organized regulatory network, such that TFs associated with environmental stimuli tended to be long-lived, while those TFs involved in computing the appropriate response to those stimuli had shorter half-lives.…”