Análise genômica revela uma estreita ligação entre a dinâmica do fator de transcrição e a arquitetura da rede reguladora

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

Raja Jothi1,5,*, S Balaji2,5,6, Arthur Wuster3, Joshua A Grochow4, Jo¨ rg Gsponer3, Teresa M Przytycka2, L Aravind2 and M Madan Babu3,*

1 Biostatistics Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA,

2 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA,

3 MRC Laboratory of Molecular Biology, Cambridge, UK and

4 Department of Computer Science, University of Chicago, Chicago, IL, USA

5 These authors contributed equally to this work

6 Present address: Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Harvard Medical
School, Boston, MA 02115, USA

* Corresponding authors. R Jothi, Biostatistics Branch, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Drive,
MD A3-03, Research Triangle Park, NC 27709, USA. Tel.:þ1 919 316 4557; Fax:þ1 301 541 4311; E-mail: jothi@mail.nih.gov or MM Babu, MRC Laboratory of Molecular Biology, Cambridge CB20QH, UK. Tel.:þ44 (0)1223 402208; Fax:þ44 (0)1223 213556; E-mail: madanm@mrc-lmb.cam.ac.uk

Received 18.11.08; accepted 7.6.09

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.

Molecular Systems Biology 5: 294; published online 18 August 2009; doi:10.1038/msb.2009.52

Subject Categories: metabolic and regulatory networks; chromatin & transcription

Keywords: dynamics; hierarchy; noise; systems biology; transcription network

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