[Research highlight] Life re-coded

Posted on 22 Jul 2011 by Andrew Hufton

In an article recently published in Science, Isaacs et al describe the replacement of all 314 TAG stop codons in the Escherichia coli genome with synonymous TAA codons, representing an unprecedented effort in large-scale genome editing.

The scientists first replaced all TAG codons in batches of ten codons across 32 separate strains using their previously-published MAGE method (Wang et al, 2009). These edited genome segments were then progressively combined using a new conjugation-based genome assembly method (CAGE). They have currently produced four strains that each have a quarter of their TAG stop codons replaced, and they hope to produce the complete TAG replacement strain in the near future. Somewhat surprisingly, no severe phenotypic consequences were observed in these replacement strains, indicating that the TAG codon is not essential, despite its near-universal presence in the genetic code of all organisms.

Indeed, the only exception to the universality of the TAG stop codon is a small selection of methanogenic archaea, and one bacterium, in which TAG encodes for the non-canonical amino acid, pyrrolysine (reviewed in Krzykci et al, 2005). Following nature’s lead, the authors hope that once they have produced the complete TAG replacement strains, they will then be able to use this free codon as a “plug-and-play” system for incorporating unnatural amino acids into proteins.

More broadly, this technology will provide an attractive alternative to wholesale chemical genome synthesis when researchers need to systematically introduce multiple genetic alterations into a genome, especially since current synthetic organism designs hew closely to natural organisms. This work may also be a first step towards creating organisms with completely rewritten genetic codes. Such fully “re-coded” organisms would have an inherent genetic “fire-wall” since they would not be able to share their genetic material via horizontal transfer or be infected by naturally occurring viruses.

Isaacs FJ, Carr PA, Wang HH, Lajoie MJ, Sterling B, Kraal L, Tolonen AC, Gianoulis TA, Goodman DB, Reppas NB, Emig CJ, Bang D, Hwang SJ, Jewett MC, Jacobson JM, Church GM (2011) Precise manipulation of chromosomes in vivo enables genome-wide codon replacement. Science 333: 348-53

Krzycki JA (2005) The direct genetic encoding of pyrrolysine. Curr Opin Microbiol 8: 706-12

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: 894-8

Updated Instructions for Authors

Posted on 27 May 2011 by Andrew Hufton

Molecular Systems Biology has recently completed a major update of its Instructions for Authors. Of particular importance, this new document now fully incorporates information about our policies regarding transparency in scientific publishing. Molecular Systems Biology, along with the other EMBO Publications journals, has made a strong commitment to promoting transparency in the editorial process, and recently began publishing a Review Process File, containing anonymous reviewers’ reports, authors’ rebuttal letters, and the editor’s decisions, with accepted manuscripts. In addition, we have been working to promote greater availability, transparency, and re-usability for scientific data associated with published works. For more details on these efforts please see our editorial, “From bench to website.”

Data transparency

For some time now, Molecular Systems Biology has allowed authors to submit source data that directly supports a particular figure panel. Links to these data are then included in the html manuscript version, directly below the associated figures, so that readers can easily discover and reuse data that is of interest to them. This feature can be used both for numeric results (e.g. supporting a graph), or for more structured data types (e.g. SBML model files). Information regarding how source data for figures should be prepared, what types of data can be accommodated, and how to submit these files in our manuscript submission system, is now included in the Instructions for Authors.

Data deposition

Molecular Systems Biology, requires that authors submit data to public repositories according to community standards, and strongly encourages them to do so before manuscript submission. Our Instructions for Authors now provides information regarding our standards for a variety of data types, including functional genomics, proteomics, molecular interactions, and computational models.

Other improvements

More detailed advice on our basic statistical analysis standards
A new Molecular Systems Biology LaTeX template and BibTeX style

These publishing policies and standards have grown out of extensive discussion with members of the scientific community, and we are eager to receive any comments or feedback you may have.

Editors’ Conference Agenda – 2011

Posted on 03 Feb 2011 by Andrew Hufton

Here is a preliminary list of conferences that the Molecular Systems Biology editors will be attending in 2011. We are looking forward seeing a lot of the Alps this year, with meetings in Innsbruck, Geneva, and Vienna. And, of course, we also looking forward to meeting Molecular Systems Biology’s readers and authors; if you are attending one of these conferences or workshops, we would be quite happy to chat with you and learn about your research.

Naturally, this schedule is subject to change, and we recognize that there are many excellent conferences that we will not be able to attend this year due to scheduling limitations.

Conference	Place	Date	Who
FEBSX-SysBio2011	Innsbruck	Feb. 26-Mar. 3	ALH
CSHL Systems Biology: Networks	Cold Spring Harbor	Mar. 22-26	TL
International Conference on Systems Biology of Human Disease	Boston	June 22-24	TL
ISMB/ECCB	Vienna	July 17-19	ALH
Gordon Conference – Cellular Systems Biology	Davidson	July 24-29	TL
The Fifth q-bio Conference on Cellular Information Processing	Santa Fe	Aug. 10-13	ALH
12th International Conference on Systems Biology	Heidelberg/Mannheim	Aug. 28-Sept. 1	TL
HUPO 2011	Geneva	Sept. 4-7	ALH
The EMBO Meeting	Vienna	Sept. 10-13	TL
EMBO \| EMBL Symposium: Structure and Dynamics of Protein Networks	Heidelberg	Oct. 13-16	TL & ALH

TL: Thomas Lemberger, ALH: Andrew L. Hufton

[Research highlight] Transcription in action

Posted on 21 Jan 2011 by Andrew Hufton

In a work just published at Nature, Churchman and Weissman (2011) describe a new method for directly capturing and sequencing elongating, or nascent, RNA transcripts. The authors then use this method to provide a detailed look at the transcriptional process in action, revealing a histone modification-dependent mechanism that constrains genome-wide antisense transcription, and pervasive transcriptional pausing and backtracking throughout genes.

The work adds to a rapidly expanding functional genomics toolkit that allows researchers to dissect evermore precise steps in the Central Dogma — the DNA to RNA to protein cascade that transforms genomic information into cellular function. See also the recent work by Cramer and colleagues that describes a method for quantifying genome-wide mRNA synthesis and decay rates (Miller et al, 2011), and the ribosome profiling technique, also developed in the Weissman lab, which can provide genome-wide views of protein translation (Ingolia et al, 2009).

Churchman LS & Weissman JS (2011) Nascent transcript sequencing visualizes transcription at nucleotide resolution. Nature 469: 368–373

Ingolia NT, Ghaemmaghami S, Newman JR, Weissman JS (2009) Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324:218-23

Miller C, Schwalb B, Maier K, Schulz D, Dümcke S, Zacher B, Mayer A, Sydow J, Marcinowski L, Dölken L, Martin DE, Tresch A, Cramer P (2011) Dynamic transcriptome analysis measures rates of mRNA synthesis and decay in yeast. Mol Syst Biol 7:458

[Research highlight] modENCODE releases extensive functional investigation of fly and worm genomes

Posted on 13 Jan 2011 by Andrew Hufton

Recently, a series of publications by members of the modENCODE consortium were released online at Science, Nature, and Genome Research. These works collectively describe a massive effort to functionally characterize and annotate the Drosophila melanogaster and Caenorhabditis elegans genomes, including in-depth analyses of genes and transcripts, epigenetic marks, transcription factor binding, and replication timing, across a range of developmental and tissue sources.

Integrated analyses of these data are described in two articles released at Science (Gerstein et al, 2010; modENCODE Consortium et al, 2010). These works provide compelling support for the existence of highly occupied target regions (HOT) regions — regions of the genomes that bind a complex mix of many transcription factors, but whose connection with gene regulation is still largely unclear — and, show that the dense epigenetic datasets can be used to segment the genomes into “chromatin states” that have distinct functional properties (see also the recent work by Filion et al, 2010)

In a related Perspective, Mark Blaxter, declares that these works have provide an important step toward the ability “to compute an organism from its genome” (Blaxter 2010). A prime example of progress toward this goal is provided by the particularly comprehensive genomic regulatory network built by the Drosophila modENCODE team, which is inferred from a combination of ChIP-based transcription factor binding, sequence motifs, epigenetic marks, and coexpression (modENCODE Consortium et al, 2010). A relatively simple linear combination of predicted regulatory inputs can predict the expression of about one quarter of the transcriptome with some accuracy. In addition, the authors find that the remaining unpredictable genes tend to have noisier expression levels, suggesting that they may be intrinsically more weakly regulated.

Blaxter M (2010) Genetics. Revealing the dark matter of the genome. Science 330:1758-9

Filion GJ, van Bemmel JG, Braunschweig U, Talhout W, Kind J, Ward LD, Brugman W, de Castro IJ, Kerkhoven RM, Bussemaker HJ, van Steensel B (2010) Systematic protein location mapping reveals five principal chromatin types in Drosophila cells. Cell 143:212-24

Gerstein MB, Lu ZJ, Van Nostrand EL, Cheng C, Arshinoff BI, Liu T, Yip KY, Robilotto R, Rechtsteiner A, Ikegami K, Alves P, Chateigner A, Perry M, Morris M, Auerbach RK, Feng X, Leng J, Vielle A, Niu W, Rhrissorrakrai K et al (2010) Integrative Analysis of the Caenorhabditis elegans Genome by the modENCODE Project. Science 330:1775-1787

modENCODE Consortium, Roy S, Ernst J, Kharchenko PV, Kheradpour P, Negre N, Eaton ML, Landolin JM, Bristow CA, Ma L, Lin MF, Washietl S, Arshinoff BI, Ay F, Meyer PE, Robine N, Washington NL, Di Stefano L, Berezikov E, Brown CD et al (2010) Identification of Functional Elements and Regulatory Circuits by Drosophila modENCODE. Science 330:1787-1797

[Research highlight] Laws of microbial growth

Posted on 29 Nov 2010 by Andrew Hufton

In a work recently published in Science, Scott et al reveal a series of microbial “growth laws” that describe simple relationships between translation, nutrition, and cellular growth. They show that these laws hold across different experimental perturbations and E. coli strains, and, ultimately, provide a phenomenological model describing the delicate balancing act cells maintain when deciding how much of their proteome to allocate to ribosome-related processes.

Scott M, Gunderson CW, Mateescu EM, Zhang Z, Hwa T (2010) Interdependence of cell growth and gene expression: origins and consequences. Science 330:1099-102

→ also see the related Perspective

Lerman J, Palsson BO (2010) Topping off a multiscale balancing act. Science 330:1058-9

q-bio 2010 Conference on Cellular Information Processing

Posted on 01 Sep 2010 by Andrew Hufton

This last August 11-14, systems biologists convened in beautiful Santa Fe, New Mexico, for the Fourth Annual q-bio Conference on Cellular Information Processing. The conference brought together a potent mix of theoretical and quantitative experimental biology across a wide range of topics. The full program and abstracts for each talk can be browsed on the conference’s Wiki page.

St. John’s College, the q-bio venue

Highlighting the value of systems-level analysis, many of the talks revealed the functional importance of features of biological systems that may often be tempting to disregard:

Thierry Emonet showed that noise in the chemotactic signaling pathways actually acts to help coordinate the bacteria’s multiple flagella. (In fact, chemotaxis and bacterial swarming were popular topics. See also the talks by Jan Liphardt, Ned Wingreen, Victor Sourjik, Bonnie Bassler, Christopher Rao, and Yi Jiang).
Talks by Anat Burger and Narendra Maheshri explored the ways that non-functional transcription factor binding sites (sites that do not directly affect gene regulation) can nonetheless have dramatic effects on the dynamics of gene regulatory circuits.
Debora Marks discussed her work showing that saturation and competition play a potentially important role in determining the efficiency of siRNA and microRNA target gene repression. (See also her recent work in Molecular Systems Biology, Arvey et al. 2010).

The conference also hosted several excellent talks on cell cycle regulation — a classical model in systems biology research — including a closing lecture by James Ferrell and a talk by John Tyson describing his detailed stochastic model of the eukaryotic cell cycle (recently published in Molecular Systems Biology, Barik et al. 2010). See also talks by Jan Skotheim, Silvia Santos, and Xiaojing Yang. Galit Lahav also provided some exciting insights into another extremely well-studied system — p53 signaling (see Loewer et al. 2010).

In addition, two researchers studying HIV1 provided some of the most thought-provoking presentations:

Leor Weinberger proposed a way to treat HIV1 with a transmissible therapeutic agent, and described both cell culture experiments demonstrating the ability of their agent to slow HIV1 propagation, and computational modeling showing how this agent could spread through the human population.

Alex Sigal used a combination of modeling and cell culture experiments to make a compelling case that direct cell-to-cell transmission of HIV1 may help maintain a low-level “smoldering infection” during anti-retroviral drug treatment.

Naturally, these are just a few highlights from the conference, which hosted many other excellent talks. Once again, we encourage you to browse the full program and abstracts on the conference’s Wiki page.

Barik D, Baumann WT, Paul MR, Novak B, Tyson JJ (2010) A model of yeast cell-cycle regulation based on multisite phosphorylation. Mol Syst Biol 6:405

Arvey A, Larsson E, Sander C, Leslie CS, Marks DS (2010) Target mRNA abundance dilutes microRNA and siRNA activity. Mol Syst Biol 6:363

Loewer A, Batchelor E, Gaglia G, Lahav G (2010) Basal Dynamics of p53 Reveal Transcriptionally Attenuated Pulses in Cycling Cells. Cell 142:89-100

[Research highlight] NF-kappaB signaling goes digital

Posted on 09 Jul 2010 by Andrew Hufton

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.

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.

[Research highlight] Cis-regulatory evolution, not so mysterious after all?

Posted on 04 Jun 2010 by Andrew Hufton

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.

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

Editors’ conference agenda

Posted on 25 May 2010 by Andrew Hufton

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 <a href = “https://www.iscb.org/ismb2010”>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