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At least 721 records · Page 40Linked to original sources

Boosting Gene Expression Clustering with System-Wide Biological Information: A Robust Autoencoder Approach

Gene expression analysis provides genome-wide insights into the transcriptional activity of a cell. One of the first computational steps in exploration and analysis of the gene expression data is clustering. With a number of standard clustering methods routinely used, most of the methods do not take prior biological information into account. In this paper, we propose a new approach for gene expression clustering analysis. The approach benefits from a new deep learning architecture, Robust Autoencoder, which provides a more accurate high-level representation of the feature sets, and from incorporating prior biological information into the clustering process. We tested our approach on two distinct gene expression datasets and compared the performance with two widely used clustering methods, hierarchical clustering and k-means, as well as with a recent deep learning clustering approach. As a result, our approach outperformed all other clustering methods on the labeled yeast gene expression dataset. Furthermore we showed that it is better in identifying the functionally common clusters than k-means on the unlabeled human gene expression dataset. The results demonstrate that our new deep learning architecture could generalize well the specific properties of gene expression profiles. Furthermore, the results confirm our hypothesis that the prior biological network knowledge could be helpful in the gene expression clustering task.

bioinformatics↗

New inhibitors of Mycobacterium tuberculosis identified using systems chemical biology

New antibiotics are needed to combat rising resistance, with new Mycobacterium tuberculosis (Mtb) drugs of highest priority. Conventional whole-cell and biochemical antibiotic screens have failed. We developed a novel strategy termed PROSPECT (PRimary screening Of Strains to Prioritize Expanded Chemistry and Targets) in which we screen compounds against pools of strains depleted for essential bacterial targets. We engineered strains targeting 474 Mtb essential genes and screened pools of 100-150 strains against activity-enriched and unbiased compounds libraries, measuring > 8.5-million chemical-genetic interactions. Primary screens identified >10-fold more hits than screening wild-type Mtb alone, with chemical-genetic interactions providing immediate, direct target insight. We identified > 40 novel compounds targeting DNA gyrase, cell wall, tryptophan, folate biosynthesis, and RNA polymerase, as well as inhibitors of a novel target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating PROSPECTs ability to yield inhibitors against novel targets which would have eluded conventional drug discovery.

microbiology↗

Discovery of the role of a SLOG superfamily biological conflict systems associated protein IodA (YpsA) in oxidative stress protection and cell division inhibition in Gram-positive bacteria

Bacteria adapt to different environments by regulating cell division and several conditions that modulate cell division have been documented. Understanding how bacteria transduce environmental signals to control cell division is critical to comprehend the global network of cell division regulation. In this article we describe a role for Bacillus subtilis YpsA, an uncharacterized protein of the SLOG superfamily of nucleotide and ligand-binding proteins, in cell division. We observed that YpsA provides protection against oxidative stress as cells lacking ypsA show increased susceptibility to hydrogen peroxide treatment. We found that increased expression of ypsA leads to cell division inhibition due to defective assembly of FtsZ, the tubulin-like essential protein that marks the sites of cell division. We showed that cell division inhibition by YpsA is linked to glucose availability. We generated YpsA mutants that are no longer able to inhibit cell division. Finally, we show that the role of YpsA is possibly conserved in Firmicutes, as overproduction of YpsA in Staphylococcus aureus also impairs cell division. Therefore, we propose ypsA to be renamed as iodA for inhibitor of division.\n\nIMPORTANCEAlthough key players of cell division in bacteria have been largely characterized, the factors that regulate these division proteins are still being discovered and evidence for the presence of yet-to-be discovered factors has been accumulating. How bacteria sense the availability of nutrients and how that information is used to regulate cell division positively or negatively is less well-understood even though some examples exist in the literature. We discovered that a protein of hitherto unknown function belonging to the SLOG superfamily of nucleotide/ligand-binding proteins, YpsA, influences cell division in Bacillus subtilis by integrating metabolic status such as the availability of glucose. We showed that YpsA is important for oxidative stress response in B. subtilis. Furthermore, we provide evidence that cell division inhibition function of YpsA is also conserved in another Firmicute Staphylococcus aureus. This first report on the role of YpsA (IodA) brings us a step closer in understanding the complete tool set that bacteria have at their disposal to regulate cell division precisely to adapt to varying environmental conditions.

microbiology↗

Differential equation based minimal model describing metabolic oscillations in Bacillus subtilis biofilms

Biofilms offer an excellent example of ecological interaction among bacteria. Temporal and spatial oscillations in biofilms are an emerging topic. In this paper we describe the metabolic oscillations in Bacillus subtilis biofilms by applying the smallest theoretical chemical reaction system showing Hopf bifurcation proposed by Wilhelm and Heinrich in 1995. The system involves three differential equations and a single bilinear term. We perform computer simulations and a detailed analysis of the system including bifurcation analysis and quasi-steady-state approximation. We also discuss the feedback structure of the system and the correspondence of the simulations to biological observations. We also specifically select parameters that are more suitable for the biological scenario of biofilm oscillations. Our theoretical work suggests potential scenarios about the oscillatory behaviour of biofilms and also serves as an application of a previously described chemical oscillator to a biological system.

systems biology↗

A global survey of System Biology-based predictions of gene-rare disease associations to enhance new diagnoses

In rare disease diagnosis, described genotype-phenotype associations are evaluated first. In the absence of strong evidence, WES and WGS provide hundred to million other genetic variants, most poorly annotated, that need to be prioritized. While several in silico approaches leverage existing gene-disease knowledge to predict novel associations, doing so in isolation can hide how different genes are represented across other predictions. We hypothesize that a global perspective, accounting for differences in the knowledge accumulated in the gene collections, can refine predictions. Using a network-based algorithm, we explored functional neighborhoods of known disease-associated genes to predict novel candidates for over 200 rare diseases. A global analysis of gene and protein family behavior across predictions identified genes and functions broadly associated with multiple conditions, 192 genes linked to a single disease and 251 genes functionally associated with specific classes of rare diseases. These findings are integrated into a gene-disease specificity score, aimed at enhancing variant prioritization and guiding geneticists in advancing candidate genes toward functional validation.

bioinformatics↗

Weak supervision of H&E slides reveals systems-level biology and functional states that govern therapeutic resistance

Precision oncology lacks scalable methods to identify the mechanisms that mediate therapeutic resistance for individual patients. Resistance often arises from focal cellular niches that are obscured by bulk profiling and costly to resolve with multi-omics. Here, we show that deep learning (DL), applied to routine histology, can localize focal tissue regions enriched for therapeutically relevant biology. Using 3111 breast cancer H&E slides with matched bulk transcriptomics, we trained weakly-supervised DL models to infer activities of immune, metabolic, and tumor-intrinsic phenotypes implicated in therapeutic resistance (AUROC>0.80; PCC>0.64). Accurate inference of these phenotypes should identify tissue regions enriched for the corresponding biological signal. Therefore, we validated phenotype inference and spatial localization with complementary analyses. Tissue-matched multiplexed immunofluorescence showed concordance between inferred immune states and corresponding cell fractions (p=0.006-0.106). Across multi-institutional cohorts, model-derived phenotypes recovered expected relationships with therapeutic outcomes (p<0.045). Finally, in a blinded evaluation, pathologists confirmed that model-derived high-attention regions were enriched for phenotype-specific morphology (p<2.408*10-5). Because evaluated phenotypes represent diverse mechanisms of resistance across therapeutic modalities, these findings provide a foundation for resistance-directed localization using therapeutic outcomes as supervision. By directing deep profiling toward model-prioritized regions, this framework could enable scalable nomination of candidate mediators of resistance for subsequent functional validation across real-world patient populations. One sentence summaryWeakly supervised deep learning localizes focal tissue regions enriched for therapeutically relevant biology in routine histology, thus offering a scalable strategy to study therapeutic resistance across large patient populations.

biophysics↗

A Novel Computational Approach for the Mining of Signature Pathways Using Species Co-occurrence Networks in Gut Microbiomes

Advances in metagenome sequencing data continue to enable new methods for analyzing biological systems. When handling microbial profile data, metagenome sequencing has proven to be far more comprehensive than traditional methods such as 16s rRNA data, which rely on partial sequences. Microbial community profiling can be used to obtain key biological signals that pave the way for better and accurate understanding of complex systems that are critical for advancing biomedical research and healthcare. There have been few attempts to uncover microbial community associations with certain health conditions. However, such attempts have mostly used partial or incomplete data to accurately capture those associations. This study introduces a novel computational approach for the identification of co-occurring microbial communities using the abundance and functional roles of species-level microbiome data. The proposed approach is then used to identify signature pathways associated with inflammatory bowel disease (IBD). Furthermore, we developed a computational pipeline to identify microbial species co-occurrences from metagenome data. When comparing IBD to a control group, we show that co-occurring communities of species are enriched for potential pathways. We also show that the identified co-occurring microbial species operate as a community to facilitate pathway enrichment. The obtained findings suggest that the proposed network model, along with the computational pipeline, provide a valuable analytical tool to analyze complex biological systems and extract pathway signatures that classify or diagnose certain health conditions. CCS CONCEPTS* Applied computing [->] Biological networks; Bioinformatics; Systems biology. ACM Reference FormatSuyeon Kim, Ishwor Thapa, and Hesham Ali. 2023. A Novel Computational Approach for the Mining of Signature Pathways Using Species Co-occurrence Networks in Gut Microbiomes. In Proceedings of ACM Conference (Conference17). ACM, New York, NY, USA, 10 pages. https://doi.org/10.1145/nnnnnnn.nnnnnnn

bioinformatics↗

Degeneracy measures in biologically plausible random Boolean networks

Biological systems show diversity in terms of the underlying network structure and the governing rules of such networks. Yet, different types of biological networks may develop similar adaptation strategies in face of environmental changes. Degeneracy refers to the ability to compensate for compromised function without the need for a redundant component in the system. Highly degenerate systems show resilience to perturbations and damage because the system can compensate for compromised function due to reconfiguration of the underlying network dynamics. Although formal definitions of degeneracy have been proposed, these definitions have only been tested in relatively simple networks involving weighted connections between network nodes. In this study, we test an information theoretic definition of degeneracy on random Boolean networks, frequently used to model gene regulatory networks. Random Boolean networks are discrete dynamical systems with binary connectivity and thus, these networks are well-suited for tracing information flow and the causal effects. By generating networks with random binary wiring diagrams, we test the effects of systematic lesioning of connections and perturbations of the network nodes on the degeneracy measure. Our analysis shows that degeneracy, on average, is the highest in networks in which ~20% of the connections are lesioned while 50% of the nodes are perturbed. Moreover, our results for the networks with no lesions and the fully-lesioned networks are comparable to the degeneracy measures from weighted networks, thus we show that the degeneracy measure is applicable to different networks. Such a generalized applicability implies that degeneracy can be used to make predictions about the variety of systems ability to recover function. Author SummaryDegeneracy - the ability of structurally different elements to perform similar functions - is a property of many biological systems. Systems exhibiting a high degree of degeneracy continue to exhibit the same macroscopic behavior following a lesion even though the underlying network dynamics are significantly different. Degeneracy thus suggests how biological systems can thrive despite changes to internal and external demands. Although degeneracy is a feature of network topologies and seems to be implicated in a wide variety of biological processes, research on degeneracy in biological networks is mostly limited to weighted networks (e.g., neural networks). To date, there has been no extensive investigation of information theoretic measures of degeneracy in other types of biological networks. In this paper, we apply existing approaches for quantifying degeneracy to random Boolean networks used for modeling biological gene regulatory networks. Using random Boolean networks with randomly generated rulesets to generate synthetic gene expression data sets, we systematically investigate the effect of network lesions on measures of degeneracy. Our results are comparable to measures of degeneracy using weighted networks, and this suggests that degeneracy measures may be a useful tool for investigating gene regulatory networks.

bioinformatics↗

Emergent digital bio-computation through spatial diffusion and engineered bacteria

Building computationally capable biological systems has long been an aim of synthetic biology. The potential utility of biocomputing devices ranges from biosafety and environmental applications to diagnosis and personalised medicine. Here we present work for the design of bacterial computers which use spatial patterning to process information. Our computers are composed of bacterial colonies which, inspired by patterning in embryo development, receive information in the form of diffusible morphogen-like signals. A computation is encoded by the physical locations of the input sources of morphogen and the output receiver colonies. We demonstrate, mathematically and with engineered Escherichia coli, the simple digital logic capability of single bacterial colonies and show how additional colonies are required to build complex functions. Inspired by electronic design automation, an algorithm for designing optimal spatial circuits computing two-level digital functions is presented. This enhances the capability of our system to complex digital functions without increasing the biological complexity. We extend our experimental system to incorporate biosensing colonies as morphogen sources, demonstrating how a diagnostic device might be constructed. Our approach will open up new ways to perform biological computation, with applications in bioengineering, biomaterials and biosensing. Ultimately, these computational bacterial communities will help us explore information processing in natural biological systems.

synthetic biology↗

Epigenetic inheritance of gene-silencing is maintained by a self-tuning mechanism based on resource competition

Biological systems can maintain memories over long timescales, with examples including memories in the brain and immune system. It is currently unknown how functional properties of memory systems, such as memory persistence, can be established by biological circuits. To address this question, we focus on transgenerational epigenetic inheritance in C. elegans. In response to a trigger, worms silence a target gene for multiple generations, resisting strong dilution due to growth and reproduction. Silencing may also be maintained indefinitely upon selection according to silencing levels. We show that these properties imply fine-tuning of biochemical rates in which the silencing system is positioned near the transition to bistability. We demonstrate that this behavior emerges from a generic mechanism based on competition for synthesis resources, which leads to self-organization around a critical state with broad silencing timescales. The theory makes distinct predictions and offers insights into the design principles of long-term memory systems.

systems biology↗

Multiplexed characterization of rationally designed promoter architectures deconstructs combinatorial logic for IPTG-inducible systems

A crucial step towards engineering biological systems is the ability to precisely tune the genetic response to environmental stimuli. In the case of Escherichia coli inducible promoters, our incomplete understanding of the relationship between sequence composition and gene expression hinders our ability to predictably control transcriptional responses. Here, we profile the expression dynamics of 8,269 rationally designed IPTG-inducible promoters that collectively explore the individual and combinatorial effects of RNA polymerase and LacI repressor binding site strengths. Using these data, we fit a statistical mechanics model that accurately models gene expression and reveals properties of theoretically optimal inducible promoters. Furthermore, we characterize three novel promoter architectures and show that repositioning binding sites within promoters influences the types of combinatorial effects observed between promoter elements. In total, this approach enables us to deconstruct relationships between inducible promoter elements and discover practical insights for engineering inducible promoters with desirable characteristics.

synthetic biology↗

Pancreatic cancer mutationscape: revealing the link between modular restructuring and intervention efficacy amidst common mutations

There is increasing evidence that biological systems are modular in both structure and function. Complex biological signaling networks such as gene regulatory networks (GRNs) are proving to be composed of subcategories that are interconnected and hierarchically ranked. These networks contain highly dynamic processes that ultimately dictate cellular function over time, as well as influence phenotypic fate transitions. In this work, we use a stochastic multicellular signaling network of pancreatic cancer (PC) to show that the variance in topological rankings of the most phenotypically influential modules implies a strong relationship between structure and function. We further show that induction of mutations alters the modular structure, which analogously influences the aggression and controllability of the disease in silico. We finally present evidence that the impact and location of mutations with respect to PC modular structure directly corresponds to the efficacy of single agent treatments in silico, because topologically deep mutations require deep targets for control.

systems biology↗

Differences in protein dosage underlie nongenetic differences in traits

Phenotypic expression of many traits varies among isogenic individuals in homogeneous environments. Intrinsic variation in the protein chaperone system affects a wide variety of traits in diverse biological systems. In C. elegans, expression of hsp-16.2 chaperone biomarkers predicts the penetrance of mutations and lifespan after heat shock. But the physiological mechanisms by which cells express different amounts of the biomarker were unknown. Here, we used an in vivo microscopy approach to dissect the mechanisms of cell-to-cell variation in hsp-16.2 biomarker expression, focusing on the intestines, which generate most signal. We found both intrinsic noise and signaling noise are low. The major axis of cell-to-cell variation in gene expression is composed of general differences in protein dosage. Thus, hsp-16.2 biomarkers reveal states of high or low effective dosages for many genes. It is possible that natural variation in protein dosage or chaperone activity may account for missing heritability of some traits.

systems biology↗

Biological oscillations without genetic oscillator or external forcing

Oscillators are fundamental to biological systems, underpinning essential processes such as cell division, circadian rhythms, and developmental cycles. While both natural and synthetic genetic oscillators have been extensively studied, oscillatory behaviors in cells can also emerge without dedicated genetic circuits. In earlier work, we uncovered sustained oscillations in phenotypic switching across diverse cellular systems and gene circuits, occurring spontaneously, without external forcing and linked them to the induction of slow-growing phenotypes. In this study, we identify the conditions that give rise to such intrinsic phenotypic instabilities, leading to population-level oscillations. We develop and analytically solve a simplified mathematical model of a stress-induced phenotype, mapping the range of continuous culture conditions that trigger oscillatory gene expression. This instability range, predicted by the model, was experimentally validated in Bacillus subtilis cultures. Our findings reveal that oscillations can arise in the complete absence of genetic oscillators or external perturbations. Although demonstrated here for a stress response in continuous culture, this phenomenon may occur in any long-term cultivation where environmental feedback links an inducer to the cellular system, broadening the landscape of possible oscillatory behaviors in microbiology and synthetic biology.

systems biology↗

Topological Entropy Correlates with the Predictive Power of Multiplexed Ensemble Reservoir Computing

Modeling nonlinear, multiscale, and transiently chaotic biological processes remains a major challenge in computational biology. Traditional deep learning models, while powerful, require large datasets and lack mechanistic interpretability, limiting their effectiveness for time-resolved biological systems. Reservoir computing (RC) offers a promising alternative by leveraging the rich transient dynamics of fixed nonlinear systems, yet standard RC architectures struggle with high-dimensional biological data and complex temporal regimes. Here, we introduce Dynamical System Machine Learning (DynML), a multiplexed reservoir framework designed to model gene-expression dynamics in systems such as liver regeneration and Drosophila embryogenesis. DynML encodes biological signals using heterogeneous Lorenz reservoirs and employs a single global readout to capture stage-dependent dynamics with high predictive accuracy. We further show that reservoir topological entropy quantitatively predicts model performance, linking dynamical richness to biological forecasting accuracy. Beyond biological time-series modeling, we demonstrate the generality of DynML on the MNIST handwritten digit classification task using a Rossler-based chaotic reservoir, showing that fixed dynamical cores with linear readouts can also support high-dimensional static classification. Overall, DynML provides a scalable, interpretable, and computationally efficient framework that unifies biological time-series modeling and conventional machine-learning tasks within a single dynamical systems paradigm. Author summaryComplex biological phenomena such as development, regeneration, and disease progression emerge from time-dependent gene-expression programs governed by nonlinear, multiscale dynamics. Capturing these dynamics remains challenging for conventional machine-learning approaches, which typically require large datasets and lack interpretability. In this study, we introduce Dynamical System Machine Learning (DynML), a modeling framework that leverages the transient dynamics of chaotic systems to learn and predict biological time series. DynML transforms gene-expression measurements into high-dimensional dynamical representations using ensembles of nonlinear reservoirs, enabling accurate prediction of future expression states with simple and interpretable linear readouts. We apply DynML to both synthetic dynamical systems and real biological datasets, including Drosophila embryonic development and human liver regeneration, where it achieves high predictive accuracy across multiple temporal transitions. Importantly, we show that the predictive performance of DynML is strongly linked to the topological entropy of the reservoir dynamics, providing a principled and quantitative measure of model expressiveness. Beyond biological time-series prediction, we demonstrate that the same dynamical framework can also classify static data, achieving strong performance on handwritten digit recognition. Together, our results establish DynML as a scalable and interpretable approach for modeling complex biological dynamics, and highlight how concepts from dynamical systems theory can guide the design of effective machine-learning models for biological data.

systems biology↗

Elucidating multi-input processing 3-node gene regulatory network topologies capable of generating striped gene expression patterns

BackgroundA central problem in developmental and synthetic biology is understanding the mechanisms by which cells in a tissue or a Petri dish process external cues and transform such information into a coherent response, e.g., a terminal differentiation state. It was long believed that this type of positional information could be entirely attributed to a gradient of concentration of a specific signaling molecule (i.e., a morphogen). However, advances in experimental methodologies and computer modeling have demonstrated the crucial role of the dynamics of a cells gene regulatory network (GRN) in decoding the information carried by the morphogen, which is eventually translated into a spatial pattern. This morphogen interpretation mechanism has gained much attention in systems biology as a tractable system to investigate the emergent properties of complex genotype-phenotype maps. MethodsIn this study, we apply a Markov chain Monte Carlo (MCMC)-like algorithm to probe the design space of three-node GRNs with the ability to generate a band-like expression pattern (target phenotype) in the middle of an arrangement of 30 cells, which resemble a simple (1-D) morphogenetic field in a developing embryo. Unlike most modeling studies published so far, here we explore the space of GRN topologies with nodes having the potential to perceive the same input signal differently. This allows for a lot more flexibility during the search space process, and thus enables us to identify a larger set of potentially interesting and realizable morphogen interpretation mechanisms. ResultsOut of 2061 GRNs selected using the search space algorithm, we found 714 classes of network topologies that could correctly interpret the morphogen. Notably, the main network motif that generated the target phenotype in response to the input signal was the type 3 Incoherent Feed-Forward Loop (I3-FFL), which agrees with previous theoretical expectations and experimental observations. Particularly, compared to a previously reported pattern forming GRN topologies, we have uncovered a great variety of novel network designs, some of which might be worth inquiring through synthetic biology methodologies to test for the ability of network design with minimal regulatory complexity to interpret a developmental cue robustly. Author summarySystems biology is a fast growing field largely powered by advances in high-performance computing and sophisticated mathematical modeling of biological systems. Based on these advances, we are now in a position to mechanistically understand and accurately predict the behavior of complex biological processes, including cell differentiation and spatial pattern formation during embryogenesis. In this article, we use an in silico approach to probe the design space of multi-input, three-node Gene Regulatory Networks (GRNs) capable of generating a striped gene expression pattern in the context of a simplified 1-D morphogenetic field.

systems biology↗

Obscured Complexity: How External Cycles Simplify the Dynamics of the Endogenous Circadian Oscillator--take the time series of body temperature records as an example

BackgroundUnderstanding circadian rhythms is crucial in various fields of biological research, as they play a fundamental role in the regulation of diverse biological processes, ranging from gene expression to physiological functions. ObjectiveThis study aims to explore the complexity of circadian rhythm signals from a biological system. Without the permission of using experimental data, the mathematical model is utilized to simulate the intricate dynamics of the body temperatures circadian rhythms and investigate the impact of parameter variation on system behavior. MethodsThe Duffing equation is constructed as the mathematical model for simulating circadian rhythms. A thorough discussion justifies the selection of the Duffing equation and establishes the proper parameter range, ensuring chaotic behavior in the system. Four different values of the driving force parameter{gamma} (0.32, 0.33, 0.34, and 0.35) are chosen to represent specific cases. Fourier analysis is employed to analyze the simulation data, revealing the frequency components present in the circadian rhythm signals. Entropy analysis along the Poincare sections is utilized to measure the systems behavior and aggregation of points. ResultsThe simulations exhibit distinct characteristics in terms of plain visualization, Fourier analysis, and entropy analysis along the Poincare sections. Under normal work sleep conditions ({gamma} = 0.35), the system demonstrates specific resetting at particular times within a total period. In shift work ({gamma} = 0.34) conditions, some of the resetting behaviour diminishes and the initial phase of the time changes. In longterm constant temperature ({gamma} = 0:33) conditions, resembles that of normal work sleep conditions, with a noticeable reset at the beginning of the period. When all external driving forces are eliminated ({gamma} = 0:32), the system undergoes multiple resets within a given period. In such circumstances, the biological clock experiences more frequent resets to adapt to the independent operations of each subsystem. Without relying on external environmental cues for regulation, the biological clock relies on frequent resetting to maintain the stability and coordination of the entire system. ConclusionThe simulations reveals variations in resetting behavior and the importance of frequent resets in the absence of external cues. The complexity arising from chaos allows the biological system to adapt and adjust to the intricacies of the external environment. The endogenous clock within the system, despite its inherent complexity, can dynamically optimize its entrainment with external cycles. However, the full complexity of the endogenous clock may be concealed within the system and not readily observable. These findings contribute to a better understanding of the complex dynamics of circadian rhythms. Future research should aim to validate these results through comparisons with experimental data.

biophysics↗

MUUMI: an R package for statistical and network-based meta-analysis for MUlti-omics data Integration

Disentangling physiopathological mechanisms of biological systems through high-level integration of omics data has become a standard procedure in life sciences. However, platform heterogeneity, batch effects, and the lack of unified methods for single- and multi-omics analyses represent relevant drawbacks that hinder the extrapolation of a meaningful biological interpretation. Statistical meta-analysis is widely used in order to integrate several omics datasets of the same type, leading to the extrapolation of robust molecular signatures within the investigated system. Conversely, statistical meta-analysis does not allow the simultaneous investigation of different molecular layers, and, therefore, the integration of multi-modal data deriving from multi-omics experiments. Although in the last few years a number of valid tools designed for multi-omics data integration have emerged, they have never been combined with statistical meta-analysis tools in a unique analytical solution in order to support meaningful biological interpretation. Network science is at the forefront of systems biology, where the inference of molecular interactomes allowed the investigation of perturbed biological systems, by shedding light on the disrupted relationships that keep the homeostasis of complex systems. Here, we present MUUMI, an R package that unifies network-based data integration and statistical meta-analysis within a single analytical framework. MUUMI allows the identification of robust molecular signatures through multiple meta-analytic methods, inference and analysis of molecular interactomes and the integration of multiple omics layers through similarity network fusion. We demonstrate the functionalities of MUUMI by presenting two case studies in which we analysed 1) 17 transcriptomic datasets on idiopathic pulmonary fibrosis (IPF) from both microarray and RNA-Seq platforms and 2) multi-omics data of THP-1 macrophages exposed to different polarising stimuli. In both examples, MUUMI revealed biologically coherent signatures, underscoring its value in elucidating complex biological processes. Availability and implementationMUUMI is freely available at https://github.com/fhaive/muumi.

bioinformatics↗