coverletter_14_feb_a - MRC Laboratory of Molecular Biology

Mr. Bean
Editor in Chief
Dear Mr. Bean
Please find enclosed our manuscript titled “Genomic Analysis Reveals Dynamic Core Formation
in the Integrated Molecular Interaction Network of Saccharomyces cerevisiae” which we would
like to submit as an article to Nature.
Over the past several decades proteins have been studied in great detail at the molecular level in
isolation. However, the realization that proteins seldom act in isolation has led scientists to study them
at the systems level in an effort to understand cellular behavior holistically. The three types of
molecular interaction networks, namely the protein-protein interaction network, transcriptional
regulatory network and the metabolic network have been studied individually and great insights have
been gained from them. Here, we present a highly composite work that puts forth several important
contributions, from the level of introducing new measures to characterize molecular networks to the
study of dynamics of such networks across different cellular conditions. These advances are listed
1. This is the first time ever that the three types of molecular interaction networks have been
integrated and studied as one. As a means to this end, we have defined a novel protein-centric
metabolic network, which is a conceptual advance in itself.
2. We also show that all the three types of molecular interaction networks organize themselves into
cores and introduce new measures to characterize such behavior. This allows us to define proteins
belonging to distinct spheres of influence in the networks.
3. We also establish that there is a significant peer-to-peer interactions among proteins belonging to
similar cores, thus defining a hierarchy in these networks.
4. We have also integrated gene-expression data as in Luscombe et al., to study the dynamics of the
integrated network across different cellular conditions. Our observation that various cellular
conditions tend to prefer specific types of interactions over others in a non-random fashion enables
one to characterize cellular states. This has been made possible by integration.
5. We also show that core-memberships are also dynamic and different proteins assume varying
levels of importance under different cellular conditions.
We strongly believe that the results presented in this work are an important contribution that opens up
new directions and advances our understanding of the structure of molecular networks significantly.
Moreover, our results have several important implications both immediately and for future research.
We also believe that the general nature of our exciting findings will be of interest to the general and
specialist readers of Nature, as there has been a lot of focus on systems biology and synthetic biology
Literature references
1. Barabasi, A., Oltvai, ZN., (2003) Nature Reviews Genetics, 5: 101-111
2. Alon, U. (2003) Science, 301: 1866-1867
3. Maslov, S., Sneppen, K. (2002) Science, 296: 910-913
4. Seidman. (1983) Social Networks, 5: 97-107
5. Newman, M. (2002) Physical Review Letters, 89: 208701
Dataset references
Protein-Protein Interaction Network
Lee, I., Date, S.V., et al. (2004) Science, 306:1555-8.
Transcriptional Regulatory Network
Luscombe, N.M., Madan Babu, M., et al. (2004) Nature, 431:308-12.
Metabolic Interaction Network
Forster, J., Famili, I., et. al. (2003) Genome Research, 13:244-53.
We would like to exclude Peer Bork (EMBL Heidelberg), Albert Barabasi (University of Notre-Dame,
USA) and Stephen Wuchty (University of Notre-Dame, USA) as referees due to conflict of interest and
would like to suggest the following as potential referees:
Dr. Nicholas Luscombe
[Specialist in Gene Networks]
European Bioinformatics Institute
Dr. George Church
[Authority in Systems Biology and Functional
Department of Biophysics
Harvard University,
Cambridge, MA
Dr. Ned Wingreen
[Expert in Mathematical Biology]
Department of Molecular Biology
Princeton University
Princeton, NJ
Dr. Edward M. Marcotte
[Expert in Functional Genomics and Systems
Department of Chemistry and Biochemistry
Institute for Molecular Biology
University of Texas at Austin
Austin, TX
Dr. Uri Alon
[Authority in Transcriptional Networks]
Dept. Molecular Cell Biology & Dept. Physics of Complex
Weizmann Institute of Science
Rehovot, Israel,
Tel: 972-8-9344448
Fax: 972-8-9344125
We would be grateful if you could expedite the review process, as there are other groups currently
working along similar lines.
Please do not hesitate to contact me if you need any further information.
M. Madan Babu