Significance The Hippo pathway restricts cell proliferation and plays key roles in organ size control tissue homeostasis. crucial step of this is the regulation transcriptional coactivators YAP/TAZ by LATS1/2 kinases. We report present study that deubiquitinase YOD1 acts as a positive regulator controlling size. significance our discovery regulatory mechanism for pathway: high density miR-21−YOD1−ITCH−LATS signaling cascade, which parallel to previously known MST1/2−LATS cascade. Data from...

Abstract Motivation: Spatio-temporal regulation of gene expression is an indispensable characteristic in the development processes all animals. ‘Master switches’, a central set regulatory genes whose states (on/off or activated/deactivated) determine specific developmental fate cell-fate specification, play pivotal role for whole processes. In this study on genome-wide integrative network analysis underlying design principles networks are examined. Results: We have found intriguing principle...

An algorithmic approach enables the simplification of complex signaling networks and identifies potential therapeutic targets.

Regulator of calcineurin 1 (RCAN1) is a key regulator the calcineurin-NFAT signaling network in organisms ranging from yeast to human, but its functional role still under debate because different roles RCAN1 have been suggested various experimental conditions. To elucidate mechanisms underlying regulatory system, we used systems approach by combining single-cell experimentation with silico simulations. In particular, found that nuclear export GSK3β, which switches on facilitative pathway,...

The co-regulation of transcription factors (TFs) has been widely observed in various species. Why is such a mechanism needed for transcriptional regulation? To answer this question, the following experiments and analyses were performed. First, examination human gene regulatory network (GRN) indicated that was significantly enriched GRN. Second, mathematical simulation an artificial showed related to biphasic dose-response patterns TFs. Third, relationship between pattern confirmed using...

Abstract In RNA virus–infected cells, retinoic acid–inducible gene-I–like receptors (RLRs) sense foreign RNAs and activate signaling cascades to produce IFN-α/β. However, not every infected cell produces IFN-α/β that exhibits cellular heterogeneity in antiviral immune responses. Using the IFN-β–GFP reporter system, we observed bimodal IFN-β production uniformly stimulated population with intracellular dsRNA. Mathematical simulation proposed strength of autocrine loop via RLR as one...

Biological systems are known to be both robust and evolvable internal external perturbations, but what causes these apparently contradictory properties? We used Boolean network modeling attractor landscape analysis investigate the evolvability robustness of human signaling network. Our results show that can divided into an core where perturbations change in state space, a neighbor have no effect on landscape. Using chemical inhibition overexpression nodes, we validated affect more strongly...

Abstract Background Network motifs provided a “conceptual tool” for understanding the functional principles of biological networks, but such have primarily been used to consider static network structures. Static however, cannot be reveal time- and region-specific traits systems. To overcome this limitation, we proposed concept “spatiotemporal motif,” spatiotemporal sequence sub-networks which are active only at specific time points body parts. Results On basis concept, analyzed developmental...

Abstract The identification of network motifs has been widely considered as a significant step towards uncovering the design principles biomolecular regulatory networks. To date, time‐invariant networks have considered. However, such approaches cannot be used to reveal time‐specific biological traits due dynamic nature systems, and hence may not applicable development, where temporal regulation gene expression is an indispensable characteristic. We propose concept “temporal sequence motifs”,...

Ubiquitination of proteins plays an essential role in various cellular processes, including protein degradation, DNA repair, and cell signaling pathways. Previous studies have shown that ubiquitination is implicated regulating pluripotency as well fate determination stem cells. To identify how affects differentiation embryonic cells, we analyzed microarray data, which are available the public domain, E3 ligases deubiquitinases whose levels changed during differentiation. Expression pja2, a...

Abstract Motivation: Gene regulatory networks (GRNs) govern cellular differentiation processes and enable construction of multicellular organisms from single cells. Although such are complex, there must be evolutionary design principles that shape the network to its present form, gaining complexity simple modules. Results: To isolate particular principles, we have computationally evolved random with a preference result either in hysteresis (switching threshold depending on current state), or...

Abstract Motivation: Viewing a cellular system as collection of interacting parts can lead to new insights into the complex behavior. In this study, we have investigated aryl hydrocarbon receptor (AhR) signal transduction pathway from such system-level perspective. AhR detects various xenobiotics, drugs or endocrine disruptors (e.g. dioxin), and mediates transcriptional regulation target genes those in cytochrome P450 (CYP450) family. On binding with 2,3,7,8-tetrachlorodibenzo-p-dioxin...

Temporal gene expression profiles have been widely considered to uncover the mechanism of cancer development and progression. Gene patterns, however, analyzed for limited stages with small samples, without proper data pre-processing, in many cases. With those approaches, it is difficult unveil over time. In this study, we two independent colorectal sample datasets, each which contained 556 566 respectively. To find specific changes according stage, applied linear mixed-effect regression...

Hysteresis can be found in many physical systems, and a hysteretic switch has been used for various mechanical electrical systems. Such created by using single positive feedback loop, as often engineering It is, however, intriguing that cellular signaling systems use coupled loops to implement the switch. A question then arises about advantage of instead simple isolated an apparently equivalent Through mathematical simulations, we determined with show enhanced switching, thereby make more...

Reverse engineering of biomolecular regulatory networks such as gene networks, protein interaction and metabolic has received an increasing attention more high-throughput time-series measurements become available. In spite various approaches developed from this motivation, it still remains a challenging subject to develop new reverse scheme that can effectively uncover the functional structure network given expression profiles (TSEPs). We propose makes use phase portraits constructed by...

Analysis of the T-cell receptor (TCR) repertoire innate CD4+ T cells selected by major histocompatibility complex (MHC) class II-dependent thymocyte–thymocyte (T-T) interaction (T-T cells) is essential for predicting characteristics antigens that bind to these and distinguishing T-T from other types cells. Using TCRmini Tg mouse model, we show TCRα chains in was extremely diverse, contrast repertoires previously described The chain sequences significantly overlapped between conventional...