Specific Regulatory Systems Research Articles

Depicting wood-based sectors to inform policymaking: A structural modeling approach centering on networks of markets

The article presents a new way of conceptualizing wood-based sectors that aims to capture intra- and inter-industrial relationships in order to enable an improved understanding of structural complexities for the design of targeted governance interventions. Building on a sociological perspective that views markets as (resource) linkages, we propose a model that represents the structure of an ideal-typical wood-based sector as a network that can be adapted to specific regulatory systems. The model-building process groups wood-based products (including services and consumers) into nodes and identifies edges that connect nodes through technological conversion pathways (i.e. markets). The structural model reveals how numerous wood-based industries are linked, providing a comprehensive depiction of the sector: a total of 1582 markets link 177 timber-based product groups across 12 different production stages. The model includes Circular Economy options and comprises multiple industries only recently considered part of the wood-based sector, such as the chemical industry. Modeling the wood-based sector when accounting for intra- and inter-industrial relationships leads to an expansion of the “traditional” sequential chain structure into a non-hierarchical network structure. The proposed structural model underscores the complexity of wood-based sectors, which results – among others – from the versatile applicability of wood across production stages. We argue that more reflection is needed on the consequences of simplifying wood-based sector structures in research assumptions. For future research related to policy goals such as circularity, the article suggests a rethinking of wood-based sectors regarding sectoral boundaries and the importance of interpreting markets in their embeddedness.

Dynamics of nucleic acid mobility.

Advances in sequencing technologies and bioinformatic analyses are accelerating the quantity and quality of data from all domains of life. This rich resource has the potential to reveal a number of important incidences with respect to possible exchange of nucleic acids. Ancient events have impacted species evolution and adaptation to new ecological niches. However, we still lack a full picture of processes ongoing within and between somatic cells, gametes, and different organisms. We propose that events linked to acceptance of alien nucleic acids grossly could be divided into 2 main routes in plants: one, when plants are exposed to extreme challenges and, the second level, a more everyday or season-related stress incited by biotic or abiotic factors. Here, many events seem to comprise somatic cells. Are the transport and acceptance processes of alien sequences random or are there specific regulatory systems not yet fully understood? Following entrance into a new cell, a number of intracellular processes leading to chromosomal integration and function are required. Modification of nucleic acids and possibly exchange of sequences within a cell may also occur. Such fine-tune events are most likely very common. There are multiple questions that we will discuss concerning different types of vesicles and their roles in nucleic acid transport and possible intracellular sequence exchange between species.

Machine Learning of All Mycobacterium tuberculosis H37Rv RNA-seq Data Reveals a Structured Interplay between Metabolism, Stress Response, and Infection.

ABSTRACTMycobacterium tuberculosis is one of the most consequential human bacterial pathogens, posing a serious challenge to 21st century medicine. A key feature of its pathogenicity is its ability to adapt its transcriptional response to environmental stresses through its transcriptional regulatory network (TRN). While many studies have sought to characterize specific portions of the M. tuberculosis TRN, and some studies have performed system-level analysis, few have been able to provide a network-based model of the TRN that also provides the relative shifts in transcriptional regulator activity triggered by changing environments. Here, we compiled a compendium of nearly 650 publicly available, high quality M. tuberculosis RNA-sequencing data sets and applied an unsupervised machine learning method to obtain a quantitative, top-down TRN. It consists of 80 independently modulated gene sets known as “iModulons,” 41 of which correspond to known regulons. These iModulons explain 61% of the variance in the organism’s transcriptional response. We show that iModulons (i) reveal the function of poorly characterized regulons, (ii) describe the transcriptional shifts that occur during environmental changes such as shifting carbon sources, oxidative stress, and infection events, and (iii) identify intrinsic clusters of regulons that link several important metabolic systems, including lipid, cholesterol, and sulfur metabolism. This transcriptome-wide analysis of the M. tuberculosis TRN informs future research on effective ways to study and manipulate its transcriptional regulation and presents a knowledge-enhanced database of all published high-quality RNA-seq data for this organism to date.IMPORTANCE Mycobacterium tuberculosis H37Rv is one of the world's most impactful pathogens, and a large part of the success of the organism relies on the differential expression of its genes to adapt to its environment. The expression of the organism's genes is driven primarily by its transcriptional regulatory network, and most research on the TRN focuses on identifying and quantifying clusters of coregulated genes known as regulons. While previous studies have relied on molecular measurements, in the manuscript we utilized an alternative technique that performs machine learning to a large data set of transcriptomic data. This approach is less reliant on hypotheses about the role of specific regulatory systems and allows for the discovery of new biological findings for already collected data. A better understanding of the structure of the M. tuberculosis TRN will have important implications in the design of improved therapeutic approaches.

A network analysis of global cephalopod trade

The global trade in cephalopods is a multi-billion dollar business involving the fishing and production of more than ten commercially valuable species. It also contributes, in whole or in part, to the subsistence and economic livelihoods of thousands of coastal communities around the world. The importance of cephalopods as a major cultural, social, economic, and ecological resource has been widely recognised, but research efforts to describe the extent and scope of the global cephalopod trade are limited. So far, there are no specific regulatory and monitoring systems in place to analyse the traceability of the global trade in cephalopods at the international level. To understand who are the main global players in cephalopod seafood markets, this paper provides, for the first time, a global overview of the legal trade in cephalopods. Twenty years of records compiled in the UN COMTRADE database were analysed. The database contained 115,108 records for squid and cuttlefish and 71,659 records for octopus, including commodity flows between traders (territories or countries) weighted by monetary value (USD) and volume (kg). A theoretical network analysis was used to identify the emergent properties of this large trade network by analysing centrality measures that revealed key insights into the role of traders. The results illustrate that three countries (China, Spain, and Japan) led the majority of global market movements between 2000 and 2019. Based on volume and value, as well as the number of transactions, 11 groups of traders were identified. The leading cluster consisted of only eight traders, who dominated the cephalopod market in Asia (China, India, South Korea, Thailand, and Vietnam), Europe (the Netherlands, and Spain), and the USA. This paper identifies the countries and territories that acted as major importers or exporters, the best-connected traders, the hubs or accumulators, the modulators, the main flow routes, and the weak points of the global cephalopod trade network over the last 20 years. This knowledge of the network is crucial to move towards an environmentally sustainable, transparent, and food-secure global cephalopod trade.

Determinant Factors and Regulatory Systems for Anthocyanin Biosynthesis in Rice Apiculi and Stigmas

Anthocyanins cause purple, brown or red colors in various tissues of rice plants, but the specific determinant factors and regulatory systems for anthocyanin biosynthesis in almost all tissues remain largely unknown. In the present study, we mapped and isolated two complementary genes, OsC1 encoding a R2R3-MYB transcriptional factor and OsDFR encoding a dihydroflavonol 4-reductase, which are responsible for the purple coloration of apiculi and stigmas in indica cultivar Xieqingzao by the map-based cloning strategy. We also identified two tissue-specific pigmentation genes, OsPa for apiculi and OsPs for stigmas, by phylogenetic analysis of all anthocyanin biosynthesis-associated bHLH transcriptional factors in maize and rice, CRISPR/Cas9 knockout and transcriptional expression analysis. The OsC1, OsPa and OsPs proteins are all localized in the nucleus while the OsDFR protein is localized in the nucleus and cytoplasm, and the OsC1 and OsDFR genes are preferentially strongly expressed in both purple-colored tissues while the OsPa and OsPs genes are preferentially strongly expressed in apiculi and stigmas, respectively. OsC1 specifically interacts with OsPa or OsPs to activate OsDFR and other anthocyanin biosynthesis genes, resulting in purple-colored apiculi or stigmas. OsC1 itself does not produce color but can produce brown apiculi when functioning together with OsPa. Loss of function of OsDFR alone leads to brown apiculi and straw-white stigmas. Genotyping and phenotyping of a panel of 176 rice accessions revealed diverse genotypic combinations of OsC1, OsDFR, OsPa and OsPs that enable accurate prediction of their apiculus and stigma pigmentation phenotypes, thus validating the general applicability of the OsC1-OsDFR-OsPa and OsC1-OsDFR-OsPs models to natural populations. Our findings disclosed the biological functions of OsC1, OsPa and OsPs, and shed light on the specific regulatory systems of anthocyanin biosynthesis in apiculi and stigmas, a further step in understanding the regulatory network of anthocyanin biosynthesis in rice.

Antimicrobial peptide GH12 suppresses cariogenic virulence factors of Streptococcus mutans

ABSTRACT Cariogenic virulence factors of Streptococcus mutans include acidogenicity, aciduricity, and extracellular polysaccharides (EPS) synthesis. The de novo designed antimicrobial peptide GH12 has shown bactericidal effects on S. mutans, but its interaction with virulence and regulatory systems of S. mutans remains to be elucidated. The objectives were to investigate the effects of GH12 on virulence factors of S. mutans, and further explore the function mechanisms at enzymatic and transcriptional levels. To avoid decrease in bacterial viability, we limited GH12 to subinhibitory levels. We evaluated effects of GH12 on acidogenicity of S. mutans by pH drop, lactic acid measurement and lactate dehydrogenase (LDH) assay, on aciduricity through survival rate at pH 5.0 and F1F0-ATPase assay, and on EPS synthesis using quantitative measurement, morphology observation, vertical distribution analyses and biomass calculation. Afterwards, we conducted quantitative real-time PCR to acquire the expression profile of related genes. GH12 at 1/2 MIC (4 mg/L) inhibited acid production, survival rate, EPS synthesis, and biofilm formation. The enzymatic activity of LDH and F1F0-ATPase was inhibited, and ldh, gtfBCD, vicR, liaR, and comDE genes were significantly downregulated. In conclusion, GH12 inhibited virulence factors of S. mutans, through reducing the activity of related enzymes, downregulating virulence genes, and inactivating specific regulatory systems.

Instrumental de análisis espacial (sistemas, soportes y modelos) aplicado a la ordenación del territorio en España

La presente aportación es una síntesis del estado de la cuestión sobre herramientas de análisis espacial en materia de ordenación del territorio y planificación regional y urbana, de cara a la labor del experto territorial en su tarea técnica en la Administración pública o en la empresa de consultoría e ingeniería, particularmente en el ámbito español. Este instrumental básico se va a referir de forma sucinta al sistema estadístico (censo demográfico e indicador de cuota de mercado), el sistema y soporte cartográfico y de SIG, el sistema normativo específico (ambiental, urbanístico y de ordenación territorial), y el uso de modelos espaciales (con referencia a las teorías de los lugares centrales y de la difusión espacial de las innovaciones). Se reflexiona, finalmente, sobre la labor del diagnóstico territorial, que ha de incluir la definición de los problemas territoriales a afrontar, la explicación de las posibles relaciones entre ellos y los objetivos perseguidos, previa a la operación del planeamiento territorial y su gobierno.

Differential expression of the three Alcanivorax borkumensis SK2 genes coding for the P450 cytochromes involved in the assimilation of hydrocarbons.

Alcanivorax borkumensis, a marine bacterium highly specialized in degrading linear and branched alkanes, plays a key ecological role in the removal of marine oil spills. It contains several alternative enzyme systems for terminal hydroxylation of alkanes, including three P450 cytochromes (P450-1, P450-2 and P450-3). The present work shows cytochrome P450-1 to be expressed from the promoter of the upstream gene fdx. Promoter Pfdx was more active when C8 -C18 n-alkanes or pristane were assimilated than when pyruvate was available. The product of ABO_0199 (named CypR) was identified as a transcriptional activator of Pfdx . The inactivation of cypR impaired growth on tetradecane, showing the importance of the fdx-P450-1 and/or cypR genes. P450-2 expression was low-level and constitutive under all conditions tested, while that of P450-3 from promoter P450-3 was much higher when cells assimilated pristane than when n-alkanes or pyruvate were available. However, the inactivation of P450-3 had no visible impact on pristane assimilation. Cyo terminal oxidase, a component of the electron transport chain, was found to stimulate promoter PP450-3 activity, but it did not affect promoters Pfdx or PP450-2 . A. borkumensis, therefore, appears to carefully coordinate the expression of its multiple hydrocarbon degradation genes using both specific and global regulatory systems.

TFE3, HSP47, and CREB3 Pathways of the Mammalian Golgi Stress Response.

The capacity of each organelle in eukaryotic cells is tightly regulated in accordance with cellular demands by specific regulatory systems, which are generically termed organelle autoregulation. The Golgi stress response is one of the systems of organelle autoregulation and it augments the capacity of Golgi function if this becomes insufficient (Golgi stress). Recently, several pathways of the mammalian Golgi stress response have been identified, specifically the TFE3, HSP47, and CREB3 pathways. This review summarizes the essential parts of the Golgi stress response from the perspective of the organelle autoregulation.

Molecular subtypes of urothelial carcinoma are defined by specific gene regulatory systems

BackgroundMolecular stratification of bladder cancer has revealed gene signatures differentially expressed across tumor subtypes. While these signatures provide important insights into subtype biology, the transcriptional regulation that governs these signatures is not well characterized.MethodsIn this study, we use publically available ChIP-Seq data on regulatory factor binding in order to link transcription factors to gene signatures defining molecular subtypes of urothelial carcinoma.ResultsWe identify PPARG and STAT3, as well as ADIRF, a novel regulator of fatty acid metabolism, as putative mediators of the SCC-like phenotype. We link the PLK1-FOXM1 axis to the rapidly proliferating Genomically Unstable and SCC-like subtypes and show that differentiation programs involving PPARG/RXRA, FOXA1/GATA3 and HOXA/HOXB are differentially expressed in UC molecular subtypes. We show that gene signatures and regulatory systems defined in urothelial carcinoma operate in breast cancer in a subtype specific manner, suggesting similarities at the gene regulatory level of these two tumor types.ConclusionsAt the gene regulatory level Urobasal, Genomically Unstable and SCC-like tumors represents three fundamentally different tumor types. Urobasal tumors maintain an apparent urothelial differentiation axis composed of PPARG/RXRA, FOXA1/GATA3 and anterior HOXA and HOXB genes. Genomically Unstable and SCC-like tumors differ from Urobasal tumors by a strong increase of proliferative activity through the PLK1-FOXM1 axis operating in both subtypes. However, whereas SCC-like tumors evade urothelial differentiation by a block in differentiation through strong downregulation of PPARG/RXRA, FOXA1/GATA3, our data indicates that Genomically Unstable tumors evade differentiation in a more dynamic manner.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0101-5) contains supplementary material, which is available to authorized users.

Evaluation of resistance mechanism against antimicrobial factors in gram positive bacteria

It is known that various antibacterial agents are observed in human for preventing bacterial infection. In this study, in order to elucidate the resistance mechanism against antimicrobial agents derived of human and bacteriocins derived of commensal bacteria, we systematically evaluated the roles of the bacteria-specific two-component systems of Staphylococcus aureus and Streptococcus mutans which colonize to different sites. Two-component systems (TCSs) are specific regulatory systems in bacteria that play an important role in sensing and adapting to the environment. As the result, four TCSs of S. aureus and three TCSs of S. mutans were associated with resistance against defensin and LL37 as antimaicrobial peptides and nisin A and nukacin ISK-1 as bacteriocins. Two TCSs that are individually associated with resistance against the bacteriocins nisin A (class I type A[I]) and nukacin ISK-1 (class I type A[II]) were identified in S. mutans, whereas one TCS is associated with main resistance against the both of nisin A and nukacin ISK-1. This result suggested that TCSs play important roles on acquisition of human- and bacteria-derived antibacterial agents. However, the resistance mechanism via TCS in S. aureus is quite different from that of in S. mutans. Additional evidence suggests that these TCSs are required for co-existence with other bacteria producing to nisin A or nukacin ISK-1, meaning that the roles of bacteriocins in the interactions between different species of commensal bacteria and the importance of TCSs in this process. Our results will highlight the roles of bacterial colonization in human being are constituted on the adaptation against antibacterial agents derived from human and commensal bacteria via TCSs.

Studying post-translational modifications with protein interaction networks

At least 46 interactome studies, broad at proteome scale or biologically more focused, have together mapped about 75,000 human protein-protein interactions (PPIs). Many of the studies addressed local interactome data paucity analyzing specific homeostatic and regulatory systems, with recent focus demonstrating the involvement of post-translational protein modification (PTM) enzyme families in a wide range of cellular functions. These datasets provided insight into binding mechanisms, the dynamic modularity of complexes or delineated combinatorial enzymatic cascades. Furthermore, the combined study of PPI and PTM dynamics has begun to reveal conditional rewiring of molecular networks through PTM-mediated recognition events. Taken together these studies highlight the utility of local and global interaction networks to functionally prioritize the many changing PTMs mapped in human cells.

Dynamic proteomics emphasizes the importance of selective mRNA translation and protein turnover during Arabidopsis seed germination.

During seed germination, the transition from a quiescent metabolic state in a dry mature seed to a proliferative metabolic state in a vigorous seedling is crucial for plant propagation as well as for optimizing crop yield. This work provides a detailed description of the dynamics of protein synthesis during the time course of germination, demonstrating that mRNA translation is both sequential and selective during this process. The complete inhibition of the germination process in the presence of the translation inhibitor cycloheximide established that mRNA translation is critical for Arabidopsis seed germination. However, the dynamics of protein turnover and the selectivity of protein synthesis (mRNA translation) during Arabidopsis seed germination have not been addressed yet. Based on our detailed knowledge of the Arabidopsis seed proteome, we have deepened our understanding of seed mRNA translation during germination by combining two-dimensional gel-based proteomics with dynamic radiolabeled proteomics using a radiolabeled amino acid precursor, namely [(35)S]-methionine, in order to highlight de novo protein synthesis, stability, and turnover. Our data confirm that during early imbibition, the Arabidopsis translatome keeps reflecting an embryonic maturation program until a certain developmental checkpoint. Furthermore, by dividing the seed germination time lapse into discrete time windows, we highlight precise and specific patterns of protein synthesis. These data refine and deepen our knowledge of the three classical phases of seed germination based on seed water uptake during imbibition and reveal that selective mRNA translation is a key feature of seed germination. Beyond the quantitative control of translational activity, both the selectivity of mRNA translation and protein turnover appear as specific regulatory systems, critical for timing the molecular events leading to successful germination and seedling establishment.

Dickeya ecology, environment sensing and regulation of virulence programme

The pectinolytic Dickeya spp. are soft-rot Gram-negative bacteria that cause severe disease in a wide range of plant species. In recent years, there has been an increase in the damage caused by Dickeya in potato crops in Europe. Soft-rot symptoms are due to the production and secretion of degradative enzymes that destroy the plant cell wall. However, an efficient colonization of the host plant requires many additional bacterial factors, including elements in the early stages allowing for the adhesion and penetration of the bacteria in the plant and different elements in the intermediate stages, involved in the adaptation to the new growth conditions encountered in the host. Dickeya pathogenicity is clearly a multifactorial process, and successful infection by these bacteria requires a temporal coordination of survival and virulence gene expression. This involves the ancestral nucleoid-associated proteins, Fis and H-NS, and modifications of DNA topology, as well as various specific regulatory systems, including a new quorum-sensing pathway and regulators that sense the bacterial metabolic status or environmental stresses. This review presents new information concerning the ecology of Dickeya and the strategies used by this bacterium to coordinate its survival and virulence programmes during infection.

Programming of respiratory health in childhood

This overview highlights recent experimental and epidemiological evidence for the programming effects of outdoor air pollution exposures during early development on lung function and chronic respiratory disorders, such as asthma and related allergic disorders. Air pollutants may impact anatomy and/or physiological functioning of the lung and interrelated systems. Programming effects may result from pollutant-induced shifts in a number of molecular, cellular, and physiological states and their interacting systems. Specific key regulatory systems susceptible to programming may influence lung development and vulnerability to respiratory diseases, including both central and peripheral components of neuroendocrine pathways and autonomic nervous system (ANS) functioning which, in turn, influence the immune system. Starting in utero, environmental factors, including air pollutants, may permanently organize these systems toward trajectories of enhanced pediatric (e.g., asthma, allergy) as well as adult disease risk (e.g., chronic obstructive pulmonary disease). Evidence supports a central role of oxidative stress in the toxic effects of air pollution. Additional research suggests xenobiotic metabolism and subcellular components, such as mitochondria are targets of ambient air pollution and play a role in asthma and allergy programming. Mechanisms operating at the level of the placenta are being elucidated. Epigenetic mechanisms may be at the roots of adaptive developmental programming. Optimal coordinated functioning of many complex processes and their networks of interaction are necessary for normal lung development and the maintenance of respiratory health. Outdoor air pollution may play an important role in early programming of respiratory health and is potentially amenable to intervention.

Biotechnological doxorubicin production: pathway and regulation engineering of strains for enhanced production

Doxorubicin (DXR) is an anthracycline-type polyketide, typically produced by Streptomyces peucetius ATCC 27952. Like the biosynthesis of other secondary metabolites in Streptomyces species, DXR biosynthesis is tightly regulated, and a very low level of DXR production is maintained in the wild-type strain. Despite that DXR is one of the most broadly used and clinically important anticancer drugs, a traditional strain improvement strategy has long been practiced via recursive random mutagenesis, with little understanding of the molecular genetic basis underlying such enhanced DXR production. Since DXR titer enhancement is imperative in the fermentation industry, attaining a comprehensive understanding and its application of the specific regulatory systems that govern secondary metabolite production is an important aspect of metabolic engineering that can efficiently improve fermentation titers. In this mini-review, various efforts to improve the titers of DXR have been summarized based on biosynthetic and regulatory studies including transcriptional and product analyses.

Improvement of secondary metabolite production in Streptomyces by manipulating pathway regulation

Titer improvement is a constant requirement in the fermentation industry. The traditional method of "random mutation and screening" has been very effective despite the considerable amount of time and resources it demands. Rational metabolic engineering, with the use of recombinant DNA technology, provides a novel, alternative strategy for titer improvement that complements the empirical method used in industry. Manipulation of the specific regulatory systems that govern secondary metabolite production is an important aspect of metabolic engineering that can efficiently improve fermentation titers. In this review, we use examples from Streptomyces secondary metabolism, the most prolific source of clinically used drugs, to demonstrate the power and utility of exploiting natural regulatory networks, in particular pathway-specific regulators, for titer improvement. Efforts to improve the titers of fredericamycin, C-1027, platensimycin, and platencin in our lab are highlighted.

Global transcriptional analysis of nitrogen fixation and ammonium repression in root-associated Pseudomonas stutzeri A1501

BackgroundBiological nitrogen fixation is highly controlled at the transcriptional level by regulatory networks that respond to the availability of fixed nitrogen. In many diazotrophs, addition of excess ammonium in the growth medium results in immediate repression of nif gene transcription. Although the regulatory cascades that control the transcription of the nif genes in proteobacteria have been well investigated, there are limited data on the kinetics of ammonium-dependent repression of nitrogen fixation.ResultsHere we report a global transcriptional profiling analysis of nitrogen fixation and ammonium repression in Pseudomonas stutzeri A1501, a root-associated and nitrogen-fixing bacterium. A total of 166 genes, including those coding for the global nitrogen regulation (Ntr) and Nif-specific regulatory proteins, were upregulated under nitrogen fixation conditions but rapidly downregulated as early as 10 min after ammonium shock. Among these nitrogen fixation-inducible genes, 95 have orthologs in each of Azoarcus sp. BH72 and Azotobacter vinelandii AvoP. In particular, a 49-kb expression island containing nif and other associated genes was markedly downregulated by ammonium shock. Further functional characterization of pnfA, a new NifA-σ54-dependent gene chromosomally linked to nifHDK, is reported. This gene encodes a protein product with an amino acid sequence similar to that of five hypothetical proteins found only in diazotrophic strains. No noticeable differences in the transcription of nifHDK were detected between the wild type strain and pnfA mutant. However, the mutant strain exhibited a significant decrease in nitrogenase activity under microaerobic conditions and lost its ability to use nitrate as a terminal electron acceptor for the support of nitrogen fixation under anaerobic conditions.ConclusionsBased on our results, we conclude that transcriptional regulation of nif gene expression in A1501 is mediated by the nif-specific and ntr gene regulatory systems. Furthermore, microarray and mutational analyses revealed that many genes of unknown function may play some essential roles in controlling the expression or activity of nitrogenase. The findings presented here establish the foundation for further studies on the physiological function of nitrogen fixation-inducible genes.

Transcriptional programs: Modelling higher order structure in transcriptional control

BackgroundTranscriptional regulation is an important part of regulatory control in eukaryotes. Even if binding motifs for transcription factors are known, the task of finding binding sites by scanning sequences is plagued by false positives. One way to improve the detection of binding sites from motifs is by taking cooperativity of transcription factor binding into account. We propose a non-parametric probabilistic model, similar to a document topic model, for detecting transcriptional programs, groups of cooperative transcription factors and co-regulated genes. The analysis results in transcriptional programs which generalise both transcriptional modules and TF-target gene incidence matrices and provide a higher-level summary of these structures. The method is independent of prior specification of training sets of genes, for example, via gene expression data. The analysis is based on known binding motifs.ResultsWe applied our method to putative regulatory regions of 18,445 Mus musculus genes. We discovered just 68 transcriptional programs that effectively summarised the action of 149 transcription factors on these genes. Several of these programs were significantly enriched for known biological processes and signalling pathways. One transcriptional program has a significant overlap with a reference set of cell cycle specific transcription factors.ConclusionOur method is able to pick out higher order structure from noisy sequence analyses. The transcriptional programs it identifies potentially represent common mechanisms of regulatory control across the genome. It simultaneously predicts which genes are co-regulated and which sets of transcription factors cooperate to achieve this co-regulation. The programs we discovered enable biologists to choose new genes and transcription factors to study in specific transcriptional regulatory systems.

POF and HP1 Bind Expressed Exons, Suggesting a Balancing Mechanism for Gene Regulation

Two specific chromosome-targeting and gene regulatory systems are present in Drosophila melanogaster. The male X chromosome is targeted by the male-specific lethal complex believed to mediate the 2-fold up-regulation of the X-linked genes, and the highly heterochromatic fourth chromosome is specifically targeted by the Painting of Fourth (POF) protein, which, together with heterochromatin protein 1 (HP1), modulates the expression level of genes on the fourth chromosome. Here we use chromatin immunoprecipitation and tiling microarray analysis to map POF and HP1 on the fourth chromosome in S2 cells and salivary glands at high resolution. The enrichment profiles were complemented by transcript profiles to examine the link between binding and transcripts. The results show that POF specifically binds to genes, with a strong preference for exons, and the HP1 binding profile is a mirror image of POF, although HP1 displays an additional “peak” in the promoter regions of bound genes. HP1 binding within genes is much higher than the basal HP1 enrichment on Chromosome 4. Our results suggest a balancing mechanism for the regulation of the fourth chromosome where POF and HP1 competitively bind at increasing levels with increased transcriptional activity. In addition, our results contradict transposable elements as a major nucleation site for HP1 on the fourth chromosome.