Regulatory Logics Research Articles

Divergence of TORC1-mediated stress response leads to novel acquired stress resistance in a pathogenic yeast.

Acquired stress resistance (ASR) enables organisms to prepare for environmental changes that occur after an initial stressor. However, the genetic basis for ASR and how the underlying network evolved remain poorly understood. In this study, we discovered that a short phosphate starvation induces oxidative stress response (OSR) genes in the pathogenic yeast C. glabrata and protects it against a severe H2O2 stress; the same treatment, however, provides little benefit in the low pathogenic-potential relative, S. cerevisiae. This ASR involves the same transcription factors (TFs) as the OSR, but with different combinatorial logics. We show that Target-of-Rapamycin Complex 1 (TORC1) is differentially inhibited by phosphate starvation in the two species and contributes to the ASR via its proximal effector, Sch9. Therefore, evolution of the phosphate starvation-induced ASR involves the rewiring of TORC1's response to phosphate limitation and the repurposing of TF-target gene networks for the OSR using new regulatory logics.

Simultaneous profiling of spatial gene expression and chromatin accessibility during mouse brain development.

The brain is a complex tissue whose function relies on coordinated anatomical and molecular features. However, the molecular annotation of the spatial organization of the brain is currently insufficient. Here, we describe microfluidic indexing-based spatial assay for transposase-accessible chromatin and RNA-sequencing (MISAR-seq), a method for spatially resolved joint profiling of chromatin accessibility and gene expression. By applying MISAR-seq to the developing mouse brain, we study tissue organization and spatiotemporal regulatory logics during mouse brain development.

Single‐cell network biology characterizes cell type gene regulation for drug repurposing and phenotype prediction in Alzheimer’s disease

AbstractBackgroundDysregulation of gene expression in Alzheimer’s disease (AD) remains elusive, especially at the cell type level. Gene regulatory network, a key molecular mechanism linking transcription factors (TFs) and regulatory elements to govern target gene expression, can change across cell types in the human brain and thus serve as a model for studying gene dysregulation in AD. However, it is still challenging to understand how cell type networks work abnormally under AD.MethodTo address this, we integrated single‐cell multi‐omics data and predicted the gene regulatory networks in AD and control for four major cell types, excitatory and inhibitory neurons, microglia and oligodendrocytes. Importantly, we applied network biology approaches to analyze the changes of network characteristics across these cell types, and between AD and control.ResultWe found that many hub TFs target different genes between AD and control (rewiring). Also, these cell‐type gene networks show strong hierarchical structures in which top TFs (master regulators) are largely common across cell types, whereas different TFs operate at the middle levels in some cell types (e.g., microglia). The regulatory logics of enriched network motifs (e.g., feed‐forward loops) further uncover cell‐type‐specific TF‐TF cooperativities in gene regulation. The cell type networks are highly modular. Several network modules with cell‐type‐specific expression changes in AD pathology are enriched with AD‐risk genes and putative targets of approved and pending AD drugs, suggesting possible cell‐type genomic medicine in AD. Finally, using the cell type gene regulatory networks, we developed machine learning models to classify and prioritize additional AD genes. We found that top prioritized genes predict AD and clinical phenotypes (e.g., cognitive impairment).ConclusionOverall, this single‐cell network biology analysis provides a comprehensive map linking genes, regulatory networks, cell types and drug targets and reveals mechanisms on cell‐type gene dysregulation in AD.

Single-cell network biology characterizes cell type gene regulation for drug repurposing and phenotype prediction in Alzheimer's disease.

Dysregulation of gene expression in Alzheimer's disease (AD) remains elusive, especially at the cell type level. Gene regulatory network, a key molecular mechanism linking transcription factors (TFs) and regulatory elements to govern gene expression, can change across cell types in the human brain and thus serve as a model for studying gene dysregulation in AD. However, AD-induced regulatory changes across brain cell types remains uncharted. To address this, we integrated single-cell multi-omics datasets to predict the gene regulatory networks of four major cell types, excitatory and inhibitory neurons, microglia and oligodendrocytes, in control and AD brains. Importantly, we analyzed and compared the structural and topological features of networks across cell types and examined changes in AD. Our analysis shows that hub TFs are largely common across cell types and AD-related changes are relatively more prominent in some cell types (e.g., microglia). The regulatory logics of enriched network motifs (e.g., feed-forward loops) further uncover cell type-specific TF-TF cooperativities in gene regulation. The cell type networks are also highly modular and several network modules with cell-type-specific expression changes in AD pathology are enriched with AD-risk genes. The further disease-module-drug association analysis suggests cell-type candidate drugs and their potential target genes. Finally, our network-based machine learning analysis systematically prioritized cell type risk genes likely involved in AD. Our strategy is validated using an independent dataset which showed that top ranked genes can predict clinical phenotypes (e.g., cognitive impairment) of AD with reasonable accuracy. Overall, this single-cell network biology analysis provides a comprehensive map linking genes, regulatory networks, cell types and drug targets and reveals cell-type gene dysregulation in AD.

An integrative transcriptional logic model of hepatic insulin resistance

Abnormalities of lipid/lipoprotein and glucose metabolism are hallmarks of hepatic insulin resistance in type 2 diabetes. The former antedate the latter, but the latter become progressively refractory to treatment and contribute to therapeutic failures. It's unclear whether the two processes share a common pathogenesis and what underlies their progressive nature. In this study, we investigated the hypothesis that genes in the lipid/lipoprotein pathway and those in the glucose metabolic pathway are governed by different transcriptional regulatory logics that affect their response to physiologic (fasting/refeeding) as well as pathophysiologic cues (insulin resistance and hyperglycemia). To this end, we obtained genomic and transcriptomic maps of the key insulin-regulated transcription factor, FoxO1, and integrated them with those of CREB, PPAR-α, and glucocorticoid receptor. We found that glucose metabolic genes are primarily regulated by promoter and intergenic enhancers in a fasting-dependent manner, while lipid genes are regulated through fasting-dependent intron enhancers and fasting-independent enhancerless introns. Glucose genes also showed a remarkable transcriptional resiliency (i.e., the ability to compensate following constitutive FoxO1 ablation through an enrichment of active marks at shared PPAR-α/FoxO1 regulatory elements). Unexpectedly, insulin resistance and hyperglycemia were associated with a "spreading" of FoxO1 binding to enhancers and the emergence of unique target sites. We surmise that this unusual pattern correlates with the progressively intractable nature of hepatic insulin resistance. This transcriptional logic provides an integrated model to interpret the combined lipid and glucose abnormalities of type 2 diabetes.

The gene regulatory system for specifying germ layers in early embryos of the simple chordate.

In animal embryos, gene regulatory networks control the dynamics of gene expression in cells and coordinate such dynamics among cells. In ascidian embryos, gene expression dynamics have been dissected at the single-cell resolution. Here, we revealed mathematical functions that represent the regulatory logics of all regulatory genes expressed at the 32-cell stage when the germ layers are largely specified. These functions collectively explain the entire mechanism by which gene expression dynamics are controlled coordinately in early embryos. We found that regulatory functions for genes expressed in each of the specific lineages contain a common core regulatory mechanism. Last, we showed that the expression of the regulatory genes became reproducible by calculation and controllable by experimental manipulations. Thus, these regulatory functions represent an architectural design for the germ layer specification of this chordate and provide a platform for simulations and experiments to understand the operating principles of gene regulatory networks.

Scoping new policy frameworks for local and community broadband networks

Over several years, locally-initiated and operated Internet infrastructure projects have attempted to provide online connectivity and simultaneously achieve various social goals. Many generations of do-it-yourself network efforts that are either wireless, such as community mesh networks, or wired, such as fiber cooperatives, exist, but in the United States scaled developments have been stalled for a variety of reasons. This research examines the history of local connectivity efforts as well as technologies designed to cultivate sharing or commons organizational approaches. By exploring instances of community-based or -oriented networking efforts, we identify some of the noneconomic benefits that might be realized with certain technologies and organizational and governance structures. Technological, social, regulatory and economic logics that have shaped historical opportunities for local responses to connectivity needs in the U.S. are not necessarily inevitable; alternative approaches do exist. Improved social and technical outcomes for connectivity may be possible, especially when catalyzed by supportive policies.

CharPlant: A De Novo Open Chromatin Region Prediction Tool for Plant Genomes

Chromatin accessibility is a highly informative structural feature for understanding gene transcription regulation, because it indicates the degree to which nuclear macromolecules such as proteins and RNAs can access chromosomal DNA. Studies have shown that chromatin accessibility is highly dynamic during stress response, stimulus response, and developmental transition. Moreover, physical access to chromosomal DNA in eukaryotes is highly cell-specific. Therefore, current technologies such as DNase-seq, ATAC-seq, and FAIRE-seq reveal only a portion of the open chromatin regions (OCRs) present in a given species. Thus, the genome-wide distribution of OCRs remains unknown. In this study, we developed a bioinformatics tool called CharPlant for the de novo prediction of OCRs in plant genomes. To develop this tool, we constructed a three-layer convolutional neural network (CNN) and subsequently trained the CNN using DNase-seq and ATAC-seq datasets of four plant species. The model simultaneously learns the sequence motifs and regulatory logics, which are jointly used to determine DNA accessibility. All of these steps are integrated into CharPlant, which can be run using a simple command line. The results of data analysis using CharPlant in this study demonstrate its prediction power and computational efficiency. To our knowledge, CharPlant is the first de novo prediction tool that can identify potential OCRs in the whole genome. The source code of CharPlant and supporting files are freely available from https://github.com/Yin-Shen/CharPlant.

Dissection of the Fgf8 regulatory landscape by in vivo CRISPR-editing reveals extensive intra- and inter-enhancer redundancy

Developmental genes are often regulated by multiple elements with overlapping activity. Yet, in most cases, the relative function of those elements and their contribution to endogenous gene expression remain poorly characterized. An example of this phenomenon is that distinct sets of enhancers have been proposed to direct Fgf8 in the limb apical ectodermal ridge and the midbrain-hindbrain boundary. Using in vivo CRISPR/Cas9 genome engineering, we functionally dissect this complex regulatory ensemble and demonstrate two distinct regulatory logics. In the apical ectodermal ridge, the control of Fgf8 expression appears distributed between different enhancers. In contrast, we find that in the midbrain-hindbrain boundary, one of the three active enhancers is essential while the other two are dispensable. We further dissect the essential midbrain-hindbrain boundary enhancer to reveal that it is also composed by a mixture of essential and dispensable modules. Cross-species transgenic analysis of this enhancer suggests that its composition may have changed in the vertebrate lineage.

Institutional logics and practice variations in sustainability reporting: evidence from an emerging field

PurposeThis paper aims to deepen the understanding of logics and practice variation in sustainability reporting in an emerging field.Design/methodology/approachThis paper adopts the institutional logics perspective and its conceptualization of society as an inter-institutional system as a theoretical lens to understand reasons for the presence of and variation in sustainability reporting. The empirical findings are based on analysis of 28 semi-structured interviews with significant social actors, and extensive documentary evidence focusing on eight companies pioneering sustainability reporting in Pakistan.FindingsThis paper confirms the presence of multiple co-existing logics in sustainability practices and lack of a dominant logic. Sustainability reporting practices are underpinned by a combination of market and corporate (business logics), state (regulatory logics), professional (transparency logics) and community (responsibility logics) institutional orders. It is argued that institutional heterogeneity (variations in logics) drives the diversity of motivations for and variations in sustainability reporting practices.Research limitations/implicationsThe paper offers a deeper theoretical explanation of how various logics dominate sustainability reporting in a field where the institutionalization of practice is in its infancy.Practical implicationsUnderstanding the conditions that influence the logics of corporate decision-makers will provide new insights into what motivates firms to engage in sustainability reporting. A broader understanding of sustainability reporting in emerging fields will foster its intended use to increase transparency, accountability and sustainability performance.Originality/valueThis paper contributes to relatively scarce but growing empirical research on emerging fields. Its major contribution lies in its focus on how multiple and conflicting institutional logics are instantiated at the organizational level, leading to wide practice variations, especially in an emerging field. In doing so, it advances the institutional logics debate on practice variations within the accounting literature.

Identifying Transcription Factor Combinations to Modulate Circadian Rhythms by Leveraging Virtual Knockouts on Transcription Networks.

SummaryThe mammalian circadian systems consist of indigenous, self-sustained 24-h rhythm generators. They comprise many genes, molecules, and regulators. To decode their systematic controls, a robust computational approach was employed. It integrates transcription-factor-occupancy and time-series gene-expression data as input. The model equations were constructed and solved to determine the transcriptional regulatory logics in the mouse transcriptome network. This hypothesizes to explore the underlying mechanisms of combinatorial transcriptional regulations for circadian rhythms in mouse. We reconstructed the quantitative transcriptional-regulatory networks for circadian gene regulation at a dynamic scale. Transcriptional-simulations with virtually knocked-out mutants were performed to estimate their influence on networks. The potential transcriptional-regulators-combinations modulating the circadian rhythms were identified. Of them, CLOCK/CRY1 double knockout preserves the highest modulating capacity. Our quantitative framework offers a quick, robust, and physiologically relevant way to characterize the druggable targets to modulate the circadian rhythms at a dynamic scale effectively.

Biogeographies: Transcending anthropocentrism in the Anthropocene

Biogeographies: Transcending anthropocentrism in the Anthropocene

Dispensation des antirétroviraux pour une durée de plus d’un mois : retour sur une recherche exploratoire qualitative

Cet article restitue les résultats d’une recherche qualitative portant sur les pratiques officinales de dispensation d’anirétroviraux (ARV) relatives à des demandes supérieures à un mois, pour un départ à l’étranger. Malgré une réglementation stricte, une cartographie montre une hétérogénéité de son application conduisant à une grande diversité des pratiques de dispensation. Cette recherche qualitative menée auprès de 22 officines à l’échelle du territoire national révèle des logiques relationnelles et réglementaires qui participent de cette absence d’uniformité des pratiques. Les notions d’« embarras », d’« engagement professionnel », de « souci réglementaire » et de « relations personnelles » avec les patients expliquent en grande partie les aménagements observés dans ce type de demande de dispensation d’ARV.

Positioning Innovation and Governance for 3D Printing in Clinical Care: An Australian Case

Aim: To position medical 3D printing practices, risk and governance as more complex than mere manufacturing so to consider the contextual network-enabled dilemmas from remediating and remanufacturing the body in professional clinical and pedagogical practice; to suggest the current regulatory logics of risk and innovation do not sufficiently acknowledge shifts to network-enabled practitioner collaborations, exemplified here via ‘chilling effects’ of closed intellectual property regimes. Methods & framework: Anonymous practitioner workshop (n:12), socio-legal critique. Results: Communicated need to acknowledge practices of medical 3D printing under socio-legal constraints. Conclusion: Consider 3D printing as communication models to sustain medical research-practice in a digital–physical age, including consideration of novel governance mechanisms such as practitioner licensing and building a medical commons with network-friendly intellectual property regime.

Signal flow control of complex signaling networks

Complex disease such as cancer is often caused by genetic mutations that eventually alter the signal flow in the intra-cellular signaling network and result in different cell fate. Therefore, it is crucial to identify control targets that can most effectively block such unwanted signal flow. For this purpose, systems biological analysis provides a useful framework, but mathematical modeling of complicated signaling networks requires massive time-series measurements of signaling protein activity levels for accurate estimation of kinetic parameter values or regulatory logics. Here, we present a novel method, called SFC (Signal Flow Control), for identifying control targets without the information of kinetic parameter values or regulatory logics. Our method requires only the structural information of a signaling network and is based on the topological estimation of signal flow through the network. SFC will be particularly useful for a large-scale signaling network to which parameter estimation or inference of regulatory logics is no longer applicable in practice. The identified control targets have significant implication in drug development as they can be putative drug targets.

Navigating the labyrinth: Academic scientists’ responses to new regulatory controls on biological material inputs to research

Academic scientists who access and use biological materials are embedded in an increasingly complex arrangement of conflicting scientific, commercial, regulatory and ethical institutional logics. This paper examines how scientists navigate and respond to these conflicting institutions. Using in-depth interviews with 40 academic scientists in four fields (marine biology, entomology, agricultural studies, ecology), we undertake a grounded theory approach to identify key categories of individual responses and the drivers of those responses. We find that scientists adopt one or more of five strategies in response to regulatory pressures: acquiescence, compromise, avoidance, defiance, and manipulation. We then leverage the institutional work literature to 1) propose a scientist response framework for understanding how individuals respond to competing logics and changing regulations and 2) demonstrate how individual cognition and effort by academic scientists reconciles (or not) conflicting institutions. We outline implications for policy and practice and conclude with a discussion of future research opportunities.

Transcriptional regulation of Rab32/38, a specific marker of pigment cell formation in Ciona robusta

Through a myriad of pigments stored in different cells, animal pigmentation represents a crucial process to face disparate environmental and ecological challenges. In vertebrates, the small GTPase Rab32 and Rab38 have a conserved role in the transport of key melanogenic enzymes, as tyrosinase (tyr) and tyrosinase-related protein (tyrp), to the melanosomes in formation. We provide a survey on Rab32/38 evolution and its regulatory logics during pigment cell formation in Ciona robusta. Our phylogeny supports the existence of a single Rab32/38 gene in tunicates, which is probably the unique transporter for tyrosinase family members in this clade. Different deletions allow us to identify the minimal cis-regulatory element able to recapitulate the endogenous gene expression during pigment cell development in C. robusta. In this conserved region, we identified two putative binding sites for the transcription factor Mitf, which is known for its role as regulator of pigmentation in vertebrates. Mutational analysis revealed that both Mitf binding sites are essential for the activity of this regulatory region and we demonstrated that Mitf misexpression is able to induce ectopic activation of the Rab32/38 regulatory region in vivo.Our results strongly indicate that Mitf is involved in the regulation of Rab32/38 activity during Ciona pigment cell development.

Resilience and housing markets: Who is it really for?

Ten years after the Global Financial Crisis, this research examines how resilience theory and rhetoric relating to the economy and housing markets has been translated into policy and practice. The methodology involves a case study of a city (Auckland) with a nationally dominant housing market and high unaffordability. Via secondary literature and a series of interviews we analyse questions connected to resilience from what, how, by whom, and discuss the implications and limits of the approach. The research demonstrates that resilience policies have focused on providing institutional stability to shock, rather than adaptation or transformation to a state that is less exposed to the systemic risks associated with flows of global capital, debt, and speculative activity. This is related to how the whole concept is vaguely defined. In the absence of guidance, institutions reinterpret resilience in a way that underpins existing market and regulatory logics, such as by increasing capital reserves or lending ratios. As a consequence, the dominant political economy, selected institutions, and to an extent, existing homeowners and speculative investors are privileged in resilience policy. By bringing these selectivities and limits to light we argue for a shift in focus away from an institutional frame to one with a deeper understanding of both the balance of an economy and the wider forces that create and reproduce housing markets.

POSTAR2: deciphering the post-transcriptional regulatory logics.

Post-transcriptional regulation of RNAs is critical to the diverse range of cellular processes. The volume of functional genomic data focusing on post-transcriptional regulation logics continues to grow in recent years. In the current database version, POSTAR2 (http://lulab.life.tsinghua.edu.cn/postar), we included the following new features and data: updated ∼500 CLIP-seq datasets (∼1200 CLIP-seq datasets in total) from six species, including human, mouse, fly, worm, Arabidopsis and yeast; added a new module ‘Translatome’, which is derived from Ribo-seq datasets and contains ∼36 million open reading frames (ORFs) in the genomes from the six species; updated and unified post-transcriptional regulation and variation data. Finally, we improved web interfaces for searching and visualizing protein–RNA interactions with multi-layer information. Meanwhile, we also merged our CLIPdb database into POSTAR2. POSTAR2 will help researchers investigate the post-transcriptional regulatory logics coordinated by RNA-binding proteins and translational landscape of cellular RNAs.

Agency and governance: Pokémon-Go and contested fun in public space

Geographic research about digital technologies sometimes frames software as a locus of social, economic, and political agency that successfully mediates a range of corporate, governmental, and institutional practices. But some digital technologies lack support from authoritative actors. How and why might some effects of software be modulated, challenged, or subverted, even if programmers’ and other stakeholders’ intentions are not malicious? This essay argues that a nuanced geographic understanding of software should encompass varieties of actors, regimes, interactions, and experiences that can limit and complicate use of everyday technologies in space and time, fortifying some digital assemblages but not others. Using content from Reddit.com, I conducted an observational discourse analysis of the popular Augmented Reality (AR) game Pokémon-Go. Reddit users reflected on occasional moments when the game conflicted with governmental, institutional, cultural, and/or locational realities and decisions that revealed the contested and fragile nature of some software-mediated practices. Three thematic areas generated considerable audience reception and engagement, which I have termed “location,” “governance,” and “encounter.” They structure the analysis that follows, along with connections to AR research in engineering sub-disciplines. It may be useful for geographers to pay greater empirical attention to everyday moments when socio-spatial practices, regulatory logics (both formal and informal), and sub-cultural tensions limit what some digital technologies and their users can do in public space.