Villar and Odom Medicine 2012, 4:11 http://genomemedicine.com/content/4/2/11

MEETING REPORT Generalizing complexity: a fruitful partnership of functional and Diego Villar*1 and Duncan T Odom1,2,3

determination of subcellular localizations for the Abstract majority of yeast . Published work from the A report on the meeting ‘Functional Genomics and laboratories of Andrews and Charles Boone (University Systems Biology 2011’, Wellcome Trust Conference of Toronto, Canada) exploited the SGA method to Centre, Wellcome Trust Genome Campus, Hinxton, produce a genome-scale landscape of genetic interactions Cambridge, UK, 29 November to 1 December, 2011. in Saccharomyces cerevisiae. Integration of this tech- Keywords Functional genomics, systems biology, nology with high-content microscopy screening of a , proteome, high-throughput biology, green fluorescent fusion library allowed con- personalized medicine struction of abundance localization networks across the yeast proteome, including flux networks of dynamic protein localization changes. Frank Holstege (University Medical Center Utrecht, e Netherlands) emphasized Despite of the astounding complexity of biological the importance of specificity and redundancy in under- systems, the history of biology is marked by attempts to standing regulatory processes. Work in his laboratory discern generalizable principles. Functional genomics employed expression changes in S. cerevisiae upon and its ultimate integration with systems biology remain single or double deletion of 165 chromatin machinery pivotal to enabling advances in experimental technology components to build a global network of chromatin inter- that provide detailed and comprehensive information action pathways, characterized by remarkably specific about networks of biological interactions. e Functional effects on for a majority of chromatin Genomics and Systems Biology 2011 conference focused regulators. A similar analysis focused on kinase/phos pha- on recent, largely unpublished developments in sequen- tase deletions revealed general principles of redundancy cing-based approaches and computational methods, in signaling networks. Holstege argued that the majority including their application to chromatin and proteome of genetic interactions are non-intuitive and underlie a systems biology. Experts at the meeting also discussed combination of partial redundancy and regulatory coup- advances in translating these findings to the clinic, with ling, allowing a single node in the network to couple/ the ultimate goal of promoting personalized medicine. uncouple two distinct responses. Here, we summarize some of the highlights presented at Jurg Bahler (University College London, UK) and Simon this exciting conference. Tavaré (University of Cambridge, UK) also presented interesting technological developments in yeast. Bahler’s Yeast leads the way in systems biology talk focused on a quantitative comparison of the fission A relatively simple genome and the availability of power- yeast and proteome using nCounter/RNA- ful methods for their genetic manipulation make yeast Seq and liquid chromatography-tandem mass spectro- models the central paradigm in systems biology. Brenda metry (LC-MS/MS), and provided quantitative support Andrews (University of Toronto, Canada) presented the for previously noted differences in mRNA/long non- latest applications of synthetic genetic array (SGA) tech- coding RNA average abundance, as well as a much higher nology to proteome localization, allowing quantitative abundance and dynamic range for proteins. Correlation of protein/mRNA abundance additionally suggests that there is considerable scope for translational (in addition *Correspondence: [email protected] 1Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson to transcriptional) control. Tavaré presented a detailed Way, Cambridge CB2 0RE, UK model of yeast replication dynamics based on time- Full list of author information is available at the end of the article course chromatin immunoprecipitation sequencing (ChIP-Seq) analysis of G1-synchronized yeast cells © 2010 BioMed Central Ltd © 2012 BioMed Central Ltd labeled with bromodeoxyuridine. Villar and Odom Genome Medicine 2012, 4:11 Page 2 of 3 http://genomemedicine.com/content/4/2/11

Functional genomics and systems biology unite in activity has led to predictive models and uncovered metazoan systems general principles of the relationship between TF occu­ In contrast to the more traditional static snapshots of pancy and chromatin marks at dynamically activated cellular state, several speakers at the conference discussed enhancers. Phil Arnold (University of Basel, Switzerland) novel functional genomics approaches to explore and discussed published work within the FANTOM Consor­ rationalize biological heterogeneity. We and others are tium (http://fantom.gsc.riken.jp/) on modeling of gene exploiting ChIP-Seq and RNA-Seq to understand the expression dynamics during monocyte differentia­tion as evolutionary principles of regulatory divergence across a linear function of predicted transcription factor binding transcription factors (TFs) and non-coding RNAs. Based sites (TFBSs). Arnold presented the adaptation of this on modeling of high-throughput RNA interference method to modeling of genome-wide profiles of chro­ (RNAi) screening, Chris Bakal (The Institute of Cancer matin marks in terms of predicted TFBSs; this points to Research, UK) elaborated on a model of morphogenesis candidate regulators for recruitment of specific chroma­ as a switch-like, versus continuous, transition between tin modifications (for example, H3K27me3). stable morphological states (analogous to molecular con­ A number of talks in the meeting addressed regulatory for­mations). Sarah Teichmann (MRC Laboratory of aspects beyond transcription, suggesting additional , UK) presented detailed analyses of scope for regulation. Lars Dolken (Cambridge University, RNA-Seq data in mouse Th2 cells that show a bimodal UK) elaborated on the kinetics of RNA processing as gene expression distribution of protein-coding inferred from a combination of progressive 4-thiouridine indicative of putatively non-functional lowly expressed tagging and RNA-Seq. Results have pointed to several genes and functional highly expressed genes. Mike White classes of splicing kinetics for coding and non-coding (University of Manchester, UK) discussed the related RNAs, including remarkably inefficient processing of concept of cell-to-cell heterogeneity and its effect in small nucleolar RNAs. Piero Carninci (RIKEN Yokohama transcriptional responses, revealed through extensive Institute, Japan) presented published and ongoing work biochemical studies and simulations based on single-cell from the FANTOM Consortium that extensively exploits observations. These findings argue for an important Deep cap analysis of gene expression (DeepCAGE) biological role of transcriptional heterogeneity and technology for transcriptome analysis. Time-course precise control of oscillatory cellular dynamics, which analysis of a panel of a hundred primary cells revealed likely contribute to population robustness by mitigating submodalities of promoter architecture associated with the effect of temporal fluctuations in paracrine signaling. tissue-specific transcription (enrichment of TATA pro­ A major highlight of the conference was the presen­ mo­ters) versus ubiquitous expression (mostly CpG tation of insightful works that employed functional promo­ters). Carninci’s results also explored dynamic and genomics to build systems biology models of metazoan spatial expression of repeat elements, pointing to transcription, moving beyond the yeast system. Ido Amit preferential retrotransposon (LINE and SINE repeats) (Weizmann Institute of Science, Israel) presented expression in nuclear fractions and a role for SINEs in unpublished work on the development and validation of regulation of protein synthesis. an Indexed high-throughput ChIP-Seq method (iChIP) to study dynamic occupancy of 40 transcription factors Moving towards personalized medicine during stimulation of mouse dendritic cells with the toll- About a third of the talks in the conference discussed like receptor agonist lipopolysaccharide, thereby model­ recent applications of functional genomics to various ing their transcriptional response to pathogens. Among pathological settings, including complementary approaches the insights made by this work is a model of a layered to genome-wide association studies, such as employing transcriptional regulation in three levels: organizers gene and protein networks for identification of candidate (pioneering TFs), controlling chromatin accessibility, disease genes (Thomas Schlitt, King’s College London, primers (control of basal expression levels) and trans­ UK) and the use of functional interaction networks for ducers (dynamic DNA-binders in response to stimuli). drug target identification (Nicola Mulder, University of Building on published efforts to model enhancer activity Cape Town, South Africa). Keith Baggerly (MD Anderson from TF occupancy during Drosophila melanogaster Cancer Center, USA) stressed the scientific and ethical mesoderm development, Eileen Furlong (European importance of reproducibility and rigorously controlled Mole­cular­ Biology Laboratory, Germany) presented a in high-throughput biology, even more so method that facilitates cell-type-specific ChIP-Seq based for research that may eventually lead to clinical trials. Of on fluorescence-activated cell sorting of covalently cross- particular originality and scientific implication was linked transgenic embryos. Integration of information on Michael Snyder’s (Stanford University, USA) presentation histone modifications and polymerase II occupancy with on his own personal profile followed over a 21 month a large collection of developmental enhancers of known period using an integrated ’ approach; his profile Villar and Odom Genome Medicine 2012, 4:11 Page 3 of 3 http://genomemedicine.com/content/4/2/11

included normal and virally infected states. This Abbreviations ChIP-Seq, chromatin immunoprecipitation-sequencing; RNA-Seq, RNA pioneering study integrated genome sequencing with sequencing; SGA, synthetic genetic array; TF, transcription factor; TFBS, profiling of the epi­genome, transcriptome, proteome, transcription factor binding site. metabolome, auto­anti­bodiome and to Competing interests correlate heteroallelic expression with disease state. The The authors declare that they have no competing interests. results illustrated the potential of integrated functional genomics to predict disease risk, with important Acknowledgements The authors thank the organizers, Alvis Brazma, Nicolas Luscombe and Tom implications for the ultimate development of Freeman, for putting together a wonderful meeting, and the colleagues personalized medicine. who gave us permission to write about their findings. We apologize to all participants whose work we could not mention due to space limitations. We Towards convergence of functional genomics and also thank Drs Claudia Kutter and Sarah Aldridge for critical reading of the manuscript and their valuable suggestions. DV and DTO are funded by Cancer systems biology Research UK, the EMBO Young Investigator Programme and the European As the cost of sequencing continues to drop and related Research Council. technologies develop, increasingly comprehensive studies Author details based on functional genomics are becoming feasible. A 1Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, major challenge remains in adequately and reproducibly Robinson Way, Cambridge CB2 0RE, UK. 2Department of Oncology, Hutchison/ MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK. 3Wellcome Trust adapting analysis and biological interpretation efforts to Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge the vast amounts of datasets generated. Nevertheless, CB10 1SA, UK. groundbreaking work presented at this exciting Published: 20 February 2012 conference exemplified the current potential of these approaches to produce systems biology models of bio­ logical interactions, explore sources of biological hetero­ doi:10.1186/gm310 geneity and emerging regulatory mechanisms, and inform Cite this article as: Villar D, Odom DT: Generalizing complexity: a fruitful partnership of functional genomics and systems biology. Genome Medicine disease prognosis and outcome, potentially tailoring 2012, 4:11. predictions to each individual.