In a report published this week at Nature, Tay et al. reveal that populations of mouse 3T3 cells exposed to TNF-α show a digital NF-κB response, where increasing TNF-α concentrations lead to a higher proportion of cells with nuclear localized NF-κB — an effect that depends, in part, on pre-existing heterogeneity within the cell population. These results provide another compelling example of the way that studies using single cell measurements are transforming our understanding of cellular signaling mechanisms. Interestingly, these results seem to contrast with another recent single-cell-based study of NF-κB dynamics (Giorgetti et al. 2010), which observed a relatively uniform population-level NF-κB response to TNF-α in human HCT116 cells, indicating that there is still much to learn about the dynamics of NF-κB signaling.

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Giorgetti L, Siggers T, Tiana G, Caprara G, Notarbartolo S, Corona T, Pasparakis M, Milani P, Bulyk ML, Natoli G (2010) Noncooperative interactions between transcription factors and clustered DNA binding sites enable graded transcriptional responses to environmental inputs. Mol Cell 37:418-28

Tay S, Hughey JJ, Lee TK, Lipniacki T, Quake SR, Covert MW (2010) Single-cell NF-kappaB dynamics reveal digital activation and analogue information processing. Nature 466:267-71

→ Also, see Cheong et al. for a history of systems biology modeling of NF-κB signaling:
Cheong R, Hoffmann A, Levchenko A (2008) Understanding NF-kappaB signaling via mathematical modeling. Mol Syst Biol 4:192.

Animal genomes are littered with conserved non-coding elements (CNEs)—most of which represent evolutionarily constrained cis-regulatory sequences—however, it is often not clear why these sequences are so exceptionally conserved, since anecdotal examples have shown that orthologous CNEs can have divergent functions in vivo (Strähle and Rastegar 2008; Elgar and Vavouri 2008). In an article recently published in Molecular Biology & Evolution, Ritter et al. compare the functional activities of 41 pairs of orthologous conserved non-coding elements (CNEs) from humans and zebrafish (2010). Interestingly, sequence similarity was found to be a poor predictor of which CNEs had conserved function. In contrast, the authors found that measuring transcription factor binding site change, instead of simple sequence divergence, improves their ability to predict functional conservation. While this set of tested CNEs remains relatively small, these results are encouraging because they suggest that as scientists move from phenomenological measures of CNE evolution to models based explicitly on binding site evolution, the patterns of cis-regulatory evolution observed within animal genomes should become far less mysterious.

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Elgar G, Vavouri T (2008) Tuning in to the signals: noncoding sequence conservation in vertebrate genomes. Trends Genet 24: 344–352

Ritter DI, Li Q, Kostka D, Pollard KS, Guo S, Chuang JH (2010) The Importance of Being Cis: Evolution of Orthologous Fish and Mammalian Enhancer Activity. Mol Biol Evol advance online publication May 21

Strähle U, Rastegar S (2008) Conserved non-coding sequences and transcriptional regulation. Brain Res Bull 75: 225–230

I spent May 14-15th at the Symposium on Integrative Network Biology and Cancer, hosted by the Institute of Cancer Research in London. The organizers, Chris Bakal and Rune Linding, managed to attract a stellar speakers list, and I had great discussions with many of the attendees. Inspired by this, I thought it could be useful to share a tentative list of conferences in 2010 that will be attended by the Molecular Systems Biology editors. If you happen to be at one these conferences, we would be delighted to meet you in person and hear about your research.

Please note that this is a tentative schedule. Moreover, please do not feel slighted if your favorite conference is not on this list. There are many high-quality conferences that we will not be able to attend this year due to scheduling limitations.

Conference	Place	Date	Who
Systems Biology & New Sequencing Technologies	Barcelona	June 16-18	TL
8th International Conference on Pathways, Networks, and Systems Medicine	Rhodes	July 9-14	TL
ISMB 2010	Boston	July 11-13	ALH
q-bio Conference on Cellular Information Processing	Santa Fe	August 11-14	ALH
The EMBO Meeting 2010	Barcelona	Sept. 4-7	TL
CSHL Personal Genomes	Cold Spring Harbor	Sept. 10-12	ALH
HUPO2010	Sydney	Sept. 19-23	TL
11th International Conference on Systems Biology	Edinburgh	Oct. 11-14	TL
EMBO Conference: From Functional Genomics to Systems Biology	Heidelberg	Nov. 13-16	ALH
Pharmacogenomics & Personalized Therapy	Cold Spring Harbor	Nov. 17-21	TL

TL: Thomas Lemberger, ALH: Andrew L. Hufton

Upshot of a series of four papers published over the last years (Gibson et al, 2010, Lartigue et al, 2009, Gibson et al, 2008, Lartigue et al, 2007), J. Craig Venter's team now reports the successful transplantation of a chemically synthesized genome into a host bacterial cell (Gibson et al, 2010). As proof of principle, a slightly altered Mycoplasma mycoides genome (JCVI-syn1.0) was synthesized, assembled and transplanted into M. capricolum recipient cells.

This achievement results from the integration of several techniques developed in previous works: 1) a hierarchical strategy to assemble, via homologous recombination in yeast, a full genome from chemically synthesized overlapping fragments (Gibson et al, 2008); 2) a method to transform a full genome into a host cell and replace the recipient genome by the donor genome ('transplantation', Lartigue et al 2007); 3) a method to transplant DNA engineered in yeast into bacteria without being inactivated by the host restriction system (Lartigue et al, 2009). Finally, in the last work, systematic debugging methods were needed to identify a single base pair deletion that prevented productive transplantation (Gibson et al 2010).

The experiment represents certainly a highly symbolic milestone. A fascinating potential of this technology, if generalized and automated, is to enable the introduction of many genomic alterations simultaneously and, thus, to be able to reprogram cellular phenotypes with non-trivial genetic combinations that would have been impossible to identify with a sequential gene by gene approach. In this sense, while technically and 'philosophically' distinct, Venter's approach appears complementary to multiplexed mutagenesis technologies that introduce simultaneously multiple modifications in a target genome (Wang et al, 2009).

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Gibson DG, Glass JI, Lartigue C, Noskov VN, Chuang RY, Algire MA, Benders GW, Montague MG, Ma L, Moodie MM, Merryman C, Vashee S, Krishnakumar R, Assad-Garcia N, Andrews-Pfannkoch C, Denisova EA, Young L, Qi, ZQ, Segall-Shapiro TH, Calvey CH, Parmar PP, Hutchison CA, Smith HO, Venter JC (2010). Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome. Science advance online publication doi: 10.1126/science.1190719

Lartigue C, Vashee S, Algire MA, Chuang RY, Benders GA, Ma L, Noskov VN, Denisova EA, Gibson DG, Assad-Garcia N, Alperovich N, Thomas DW, Merryman C, Hutchison CA 3rd, Smith HO, Venter JC, Glass JI (2009). Creating bacterial strains from genomes that have been cloned and engineered in yeast. Science 325:1693

Gibson DG, Benders GA, Andrews-Pfannkoch C, Denisova EA, Baden-Tillson H, Zaveri J, Stockwell TB, Brownley A, Thomas DW, Algire MA, Merryman C, Young L, Noskov VN, Glass JI, Venter JC, Hutchison CA 3rd, Smith HO (2008). Complete chemical synthesis, assembly, and cloning of a Mycoplasma genitalium genome. Science 319:1215

Lartigue C, Glass JI, Alperovich N, Pieper R, Parmar PP, Hutchison CA 3rd, Smith HO, Venter JC (2007). Genome transplantation in bacteria: changing one species to another. Science 317:632

Wang HH, Isaacs FJ, Carr PA, Sun ZZ, Xu G, Forest CR, Church GM (2009). Programming cells by multiplex genome engineering and accelerated evolution. Nature 460:894