Interactive Map Research Articles

Towards clinically relevant dose ratios for Cabamiquine and Pyronaridine combination using P. falciparum field isolate data

The selection and combination of dose regimens for antimalarials involve complex considerations including pharmacokinetic and pharmacodynamic interactions. In this study, we use immediate ex vivo P. falciparum field isolates to evaluate the effect of cabamiquine and pyronaridine as standalone treatments and in combination therapy. We feed the data into a pharmacometrics model to generate an interaction map and simulate meaningful clinical dose ratios. We demonstrate that the pharmacometrics model of parasite growth and killing provides a detailed description of parasite kinetics against cabamiquine-susceptible and resistant parasites. Pyronaridine monotherapy provides suboptimal killing rates at doses as high as 720 mg. In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients. The described methodology that combines a rapid, 3R-compliant in vitro method and modelling to set meaningful doses for new antimalarials could contribute to clinical drug development.

Poetry unveiled: Multimodality and aesthetic responses as a fresh approach to teaching and reading verse

AbstractIn secondary English classrooms, poetry is often a text that is least liked because it is viewed as being “inaccessible,” reserved for the elite, and/or too abstract. Part of the reason for this also lies in the traditional, colonial structures of introducing poetry such as relying on canonical texts and close reading analysis. Yet, outside of the classroom poetry is used in more accessible and engaging manners. With the advancements of technology, there also includes multimodal ways in which to read and write poetry that could be much more interesting for both educators and youth. This paper opens a discussion to consider multimodal and aesthetic responses to including poetry such as using digital apps like PhoneMe, a free accessible platform that allows users to post their written poems, record themselves reciting poems, and pin their poems directly on to an interactive digital map. The uniqueness of PhoneMe—a layered multimodal approach—can provide a more engaging way to teach and learn poetry.

Fault diagnosis method for oil-immersed transformers integrated digital twin model

To address the problems of low accuracy in fault diagnosis of oil-immersed transformers, poor state perception ability and real-time collaboration during diagnosis feedback, a fault diagnosis method for transformers based on the integration of digital twins is proposed. Firstly, fault sample balance is achieved through Iterative Nearest Neighbor Oversampling (INNOS), Secondly, nine-dimensional ratio features are extracted, and the correlation between dissolved gases in oil and fault types is established. Then, sparse principal component analysis (SPCA) is used for feature fusion and dimensionality reduction. Finally, the Aquila Optimizer (AO) is introduced to optimize the parameters of the Kernel Extreme Learning Machine (KELM), establishing the optimal AO-KELM diagnosis model. The final fault diagnosis accuracy reaches 98.1013%. Combining transformer digital twin models, real-time interaction mapping between physical entities and virtual space is achieved, enabling online diagnosis of transformer faults. Experimental results show that the method proposed in this paper has high diagnostic accuracy and strong stability, providing reference for the intelligent operation and maintenance of transformers.

Monitoring and interactive mapping of illegal environmental activities on the example of Slovakia

Monitoring and interactive mapping of illegal environmental activities on the example of Slovakia

[Translated article] Bibliometric Study of the Advances Made in Clinical Dermatological Research in Spain from 2015 through 2021: Update of the MaIND Project and Interactive Online Map

IntroductionA clinical dermatological research was conducted in Spain from 2005 through 2014 as part of the MaIND project with the provinces or centers with the highest number of published articles. However, a low level of evidence in scientific production was confirmed as the overall result. The aim of this study is to update the Spanish clinical dermatological research in bibliometric terms from 2015 through 2021 with comparisons between both periods of time. Material and methodsWe conducted a bibliometric study to replicate the methodology used in the article to be updated. We included articles whose corresponding authors’ affiliation was a Spanish dermatological center, which met the criteria for clinical research in dermatology, including a level of evidence ≤4. ResultsA total of 1,674 out of the 10,199 articles met the inclusion criteria. An interactive map representing quantitative and qualitative indicators calculated for the 2005-2021 is presented here. In the study period, we found an increasing trend both in the number of published articles (P<.002) and in the mean number of citation-years per article (P<.01). A total of 22 of the articles had a level of evidence >4, with a positive trend towards more articles having a higher level of evidence (P<.03). ACTAS DERMOSIFILOGRÁFICAS still maintains its position as the journal with the highest number of articles received (18%, a total of 302 articles). ConclusionsThe results of this study show that, in Spain, the scientific production of dermatology represents an upward trend in quantity, impact, and level of evidence.

Resolving 3-Dimensional Genomic Landscape of CD4+ T Cells in the Peripheral Blood of Patients with Psoriasis

A precise regulation of gene expression depends on the accuracy of the 3-dimensional (3D) structure of chromatin; however, the effects of the 3D genome on gene expression in psoriasis remain unknown. In this study, we conducted Hi-C and RNA sequencing on CD4+ T cells collected from 5 patients with psoriasis and 3 healthy controls and constructed a comprehensive 3D chromatin interaction map to delineate the genomic hierarchies, including A/B compartments, topologically associated domains, and chromatin loops. Then, the specific superenhancers related to psoriasis were identified by Hi-C and H3K27ac chromatin immunoprecipitation sequencing data. Subsequently, comprehensive analyses were carried out on the differentially expressed genes that are associated with altered topologically associated domains, loops, and superenhancers in psoriasis. Finally, we screened the candidate target genes and examined the potential functional SNP in psoriasis affected by disruptions of the spatial organization. This study provides a comprehensive reference for examining the 3D genome interactions in psoriasis and elucidating the interplay between spatial organization disruption and gene regulation. We hope that our findings can help clarify the mechanisms underlying the pathogenesis of psoriasis and shed light on the role of 3D genomic structure, therefore informing potential therapeutic approaches.

Abstract P364: Chromatin Interactions Between Regulatory Elements Influence Gene Expression in Human iPSC-Derived Endothelial and Vascular Smooth Muscle Cells

Most SNPs associated with blood pressure (BP) are located in noncoding regions of the human genome, where they may regulate gene expression in BP-relevant cell types. However, the mechanisms by which these SNPs influence BP regulation are unclear. To address this, we developed comprehensive epigenomic landscapes in human induced pluripotent stem cell (iPSC)-derived endothelial cells (iECs) and vascular smooth muscle cells (iVSMCs), incorporating DNA methylation analysis (RRBS), transcriptome analysis (RNA-seq), chromatin state profiling (ATAC-seq), and chromatin interaction mapping (Micro-C). We identified 5301, 8916, and 6046 chromatin loops in iECs and 5329, 7598, and 5228 loops in iVSMCs at 4, 8, and 16 kb resolutions (FDR &lt; 0.05) respectively based on the Micro-C analysis. Remarkably, 82.4% and 83.8% of these chromatin contact regions in iECs and iVSMCs, respectively, harbored at least one known regulatory element such as an enhancer, promoter, or transcription factor binding site. Notably, 109 and 119 BP-associated SNPs were found within the chromatin contact regions of iECs and iVSMCs, respectively. We further investigated chromatin contact regions that involved interactions of regulatory elements. In both iECs and iVSMCs, lower methylation levels were observed in chromatin contact regions involving promoter-promoter (PP) and enhancer-promoter (EP) interactions, compared to enhancer-enhancer (EE), enhancer-transcription factor binding site (ET), and promoter-transcription factor binding site (PT) interactions. Additionally, greater chromatin accessibility was observed in chromatin contact regions involving PP and EP interactions. BP-associated SNPs were significantly enriched in chromatin contact regions involving PP and EP interactions. Moreover, genes proximal to chromatin contact regions involving PP or EP interactions exhibited higher expression than those near EE or other regulatory element interactions. These findings offer new insights into how chromatin interactions between regulatory elements define transcriptional states in human endothelial and vascular smooth muscle cells, providing a novel basis for understanding the genetic regulation of BP.

Machine learning unravels inherent structural patterns in Escherichia coli Hi-C matrices and predicts chromosome dynamics.

High dimensional nature of the chromosomal conformation contact map ('Hi-C Map'), even for microscopically small bacterial cell, poses challenges for extracting meaningful information related to its complex organization. Here we first demonstrate that an artificial deep neural network-based machine-learnt (ML) low-dimensional representation of a recently reported Hi-C interaction map of archetypal bacteria Escherichia coli can decode crucial underlying structural pattern. The ML-derived representation of Hi-C map can automatically detect a set of spatially distinct domains across E. coli genome, sharing reminiscences of six putative macro-domains previously posited via recombination assay. Subsequently, a ML-generated model assimilates the intricate relationship between large array of Hi-C-derived chromosomal contact probabilities and respective diffusive dynamics of each individual chromosomal gene and identifies an optimal number of functionally important chromosomal contact-pairs that are majorly responsible for heterogenous, coordinate-dependent sub-diffusive motions of chromosomal loci. Finally, the ML models, trained on wild-type E. coli show-cased its predictive capabilities on mutant bacterial strains, shedding light on the structural and dynamic nuances of ΔMatP30MM and ΔMukBEF22MM chromosomes. Overall our results illuminate the power of ML techniques in unraveling the complex relationship between structure and dynamics of bacterial chromosomal loci, promising meaningful connections between ML-derived insights and biological phenomena.

Comparable clinical advantages identification of three formulae on rheumatic disease using a modular-based network proximity approach

Ethnopharmacological relevanceHerbal formulae have been used in China for thousands of years but have unclear clinical positioning and unknown characteristic indications make it difficult to determine their specific application in various diseases, which seriously hamper their clinical value. Identifying the precise clinical positioning and clinical advantages of similar formulae for related diseases is a critical issue. Aim of this studyTo develop a methodology based on modular pharmacology to determine the clinical advantages and precise clinical position of similar formulae. Materials and methodsIn this study, we proposed a modular-based network proximity approach to explore drug repositioning and clinical advantages of three formulae, Shirebi tablets (SRB), Yuxuebi capsules (YXB), and Wangbifukang granules (WBFK), for rheumatic disease. First, we constructed a rheumatology target network, and modules were obtained using the cluster tool molecular complex detection (MCODE). Based on the modular interaction map established by a quantitative approach for inter-module coordination and its transition (IMCC), using a targeting rate (TR) matrix to identify targeted modules of three formulae. Moreover, the network proximity Z-score and Jaccard similarity coefficient were used to identify potential optimal symptomatic indications and related diseases using three formulae. At the same time, the driver genes for SRB and gouty arthritis were identified by flow centrality and shortest distance, and the epresentative driver genes were validated by in vivo experiments. Results32 modules were obtained using the MCODE method. 4, 4, and 14 characteristic targeted modules of SRB, YXB, and WBFK, respectively, were identified using a targeting rate (TR) matrix. Module 2, 16, and 19 were targeted by both SRB and WBFK. The common effects of SRB and WBFK focused on inflammatory response and innate immune response, YXB was found to be involved in the collagen catabolic process, transmembrane receptor protein serine/threonine kinase signaling pathway. Moreover, potential optimal symptomatic indications and representative related diseases were identified for three formulae: SRB was significantly associated with GA (Z = −20.26); YXB was significantly associated with AS (Z = −4.532), MI (Z = −29.11), RhFv (Z = −6.945), OA (Z = −39.97), and GA (Z = −13.03); and WBFK was significantly associated with MI (Z = −205.5), SLE (Z = −37.65), RhFv (Z = −42.45), and GA (Z = −17.24). Finally, 8 driver genes for SRB and gouty arthritis were identified,the representative driver genes TRAF6 and NFE2L1 were validated by in vivo experiments. ConclusionsThe modular-based network proximity approach proposed in this study may provide a new perspective for the precise drug repositioning and clinical advantages of similar formulae in disease treatment.

Interpretable machine learning tools to analyze PM2.5 sensor network data so as to quantify local source impacts and long-range transport

Sensor networks provide spatially resolved information about the time variation of PM2.5 concentrations in urban areas around the world. With relatively simple improvements to the control of the temperature and humidity of incoming air, and with proper quality assurance and calibration protocols, a low cost monitor was developed that provides measurements that were highly correlated with a reference PM2.5 monitor. These have sufficient resolution and reliability to quantify small differences within an urban area. Nevertheless, many sites report similar concentrations and it can be difficult to interpret the results or distinguish local from regional effects. Generalized Additive Models are an effective Machine Learning method to distinguish the impact of factors across very different scales. As a type of Interpretable Machine Learning / eXplainable Artificial Intelligence, they provide direct information on the link between specific factors and PM2.5 concentrations. GAM simulations were developed for sensors located around Dhaka, Bangladesh, for both the dry and the wet seasons. The simulations show that the largest contributor to high PM2.5 concentration variations across both urban and peri-urban sites is the boundary layer height which represent the vertical mixing of the urban plume. Using Trajectory Cluster Concentration Impacts, the simulations showed that robust estimates of long-range transport could be obtained from measurements located within a polluted environment, and the model further showed that enhancements of more than 40μg/m3 were associated with air transport from the Indo-Gangetic Plain in the dry season. Finally, interaction maps of the effect of horizontal wind speed and direction showed that these could be associated with up to +/−20 % variation in PM2.5 from site to site. Most of the enhancements are related to very calm winds and appear to be more strongly associated with road emissions than with point sources. Overall, the sensor network shows that air is polluted throughout the Dhaka area and into the peripheries, and that a multipronged approach will be needed to improve air quality for its inhabitants.

The power of interactive maps for communicating spatio-temporal data to health professionals.

While more and more health-related data is being produced and published every day, few of it is being prepared in a way that would be beneficial for daily use outside the scientific realm. Interactive visualizations that can slice and condense enormous amounts of multi-dimensional data into easy-to-digest portions are a promising tool that has been under-utilized for health-related topics. Here we present two case studies for how interactive maps can be utilized to make raw health data accessible to different target audiences: i) the European Notifiable Diseases Interactive Geovisualization (ENDIG) which aims to communicate the implementation status of disease surveillance systems across the European Union to public health experts and decision makers, and ii) the Zoonotic Infection Risk in Twente-Achterhoek Map (ZIRTA map), which aims to communicate information about zoonotic diseases and their regional occurrence to general practitioners and other healthcare providers tasked with diagnosing infectious diseases on a daily basis. With these two examples, we demonstrate that relatively straight-forward interactive visualization approaches that are already widely used elsewhere can be of benefit for the realm of public health.

Single-pulse ultrafast real-time simultaneous planar imaging of femtosecond laser-nanoparticle dynamics in flames

The creation of carbonaceous nanoparticles and their dynamics in hydrocarbon flames are still debated in environmental, combustion, and material sciences. In this study, we introduce single-pulse femtosecond laser sheet-compressed ultrafast photography (fsLS-CUP), an ultrafast imaging technique specifically designed to shed light on and capture ultrafast dynamics stemming from interactions between femtosecond lasers and nanoparticles in flames in a single-shot. fsLS-CUP enables the first-time real-time billion frames-per-second (Gfps) simultaneous two-dimensional (2D) imaging of laser-induced fluorescence (LIF) and laser-induced heating (LIH) that are originated from polycyclic aromatic hydrocarbons (PAHs) and soot particles, respectively. Furthermore, fsLS-CUP provides the real-time spatiotemporal map of femtosecond laser-soot interaction as elastic light scattering (ELS) at an astonishing 250 Gfps. In contrast to existing single-shot ultrafast imaging approaches, which are limited to millions of frames per second only and require multiple laser pulses, our method employs only a single pulse and captures the entire dynamics of laser-induced signals at hundreds of Gfps. Using a single pulse does not change the optical properties of nanoparticles for a following pulse, thus allowing reliable spatiotemporal mapping. Moreover, we found that particle inception and growth are derived from precursors. In essence, as an imaging modality, fsLS-CUP offers ultrafast 2D diagnostics, contributing to the fundamental understanding of nanoparticle’s inception and broader applications across different fields, such as material science and biomedical engineering.

Chromosome-level genome assembly and annotation of the Spinibarbus caldwelli

Spinibarbus caldwelli is an important freshwater economic fish in China. Owing to uncontrolled fishing, wild resources of S. caldwelli have decreased rapidly and may be on the verge of extinction. In this study, utilizing single-molecule real-time (SMRT) sequencing technology and chromatin interaction mapping (Hi-C) technologies, we assembled the first chromosome-scale genome for S. caldwelli about 1.77 Gb in size, with a contig N50 length of 11.83 Mb and scaffold N50 length of 33.91 Mb. In total 1.72 Gb (97.01%) of the contig sequences were anchored onto fifty chromosomes with the longest scaffold being 56.20 Mb. Furthermore, proximately 49.41% of the genome was composed of repetitive elements. In total, 49,377 protein-coding genes were predicted, of which 47,724 (96.65%) genes have been functionally annotated. The high-quality chromosome-level reference genome and annotation are vital for supporting basic genetic studies and will be contribute to genetic structure, functional elucidation, evolutionary inquiry, and germplasm conservation for S. caldwelli.

Emotional palette: a computational mapping of aesthetic experiences evoked by visual art

Despite the evolutionary history and cultural significance of visual art, the structure of aesthetic experiences it evokes has only attracted recent scientific attention. What kinds of experience does visual art evoke? Guided by Semantic Space Theory, we identify the concepts that most precisely describe people’s aesthetic experiences using new computational techniques. Participants viewed 1457 artworks sampled from diverse cultural and historical traditions and reported on the emotions they felt and their perceived artwork qualities. Results show that aesthetic experiences are high-dimensional, comprising 25 categories of feeling states. Extending well beyond hedonism and broad evaluative judgments (e.g., pleasant/unpleasant), aesthetic experiences involve emotions of daily social living (e.g., “sad”, “joy”), the imagination (e.g., “psychedelic”, “mysterious”), profundity (e.g., “disgust”, “awe”), and perceptual qualities attributed to the artwork (e.g., “whimsical”, “disorienting”). Aesthetic emotions and perceptual qualities jointly predict viewers’ liking of the artworks, indicating that we conceptualize aesthetic experiences in terms of the emotions we feel but also the qualities we perceive in the artwork. Aesthetic experiences are often mixed and lie along continuous gradients between categories rather than within discrete clusters. Our collection of artworks is visualized within an interactive map (https://barradeau.com/2021/emotions-map/), revealing the high-dimensional space of aesthetic experiences associated with visual art.

Atomic resolution map of the solvent interactions driving SOD1 unfolding in CAPRIN1 condensates

Biomolecules can be sequestered into membrane-less compartments, referred to as biomolecular condensates. Experimental and computational methods have helped define the physical-chemical properties of condensates. Less is known about how the high macromolecule concentrations in condensed phases contribute "solvent" interactions that can remodel the free-energy landscape of other condensate-resident proteins, altering thermally accessible conformations and, in turn, modulating function. Here, we use solution NMR spectroscopy to obtain atomic resolution insights into the interactions between the immature form of superoxide dismutase 1 (SOD1), which can mislocalize and aggregate in stress granules, and the RNA-binding protein CAPRIN1, a component of stress granules. NMR studies of CAPRIN1:SOD1 interactions, focused on both unfolded and folded SOD1 states in mixed phase and demixed CAPRIN1-based condensates, establish that CAPRIN1 shifts the SOD1 folding equilibrium toward the unfolded state through preferential interactions with the unfolded ensemble, with little change to the structure of the folded conformation. Key contacts between CAPRIN1 and the H80-H120 region of unfolded SOD1 are identified, as well as SOD1 interaction sites near both the arginine-rich and aromatic-rich regions of CAPRIN1. Unfolding of immature SOD1 in the CAPRIN1 condensed phase is shown to be coupled to aggregation, while a more stable zinc-bound, dimeric form of SOD1 is less susceptible to unfolding when solvated by CAPRIN1. Our work underscores the impact of the condensate solvent environment on the conformational states of resident proteins and supports the hypothesis that ALS mutations that decrease metal binding or dimerization function as drivers of aggregation in condensates.

An Integrated Approach Using Network Pharmacology and Experimental Validation to Reveal the Therapeutic Mechanism of Weifuchun in Treating Gastric Cancer.

Gastric cancer (GC) is a prevalent malignancy affecting the gastrointestinal tract. Weifuchun (WFC), a Chinese herbal prescription comprising red ginseng, Isodon amethystoides, and Fructus aurantii, is widely used in China for various chronic stomach disorders. However, its therapeutic role and mechanisms in treating GC remain unexplored. In a randomized, controlled, single-blind trial involving postoperative stages II and III GC patients, we compared adjuvant chemotherapy plus WFC (chemo plus WFC group) to adjuvant chemotherapy alone (chemo group) over 6 months. We assessed recurrence and metastasis rates and used systematic pharmacology to predict WFC's active components, screen target genes, and construct network interaction maps, were validated through in vitro experiments. The combined therapy significantly reduced 2-year recurrence and metastasis rates. We identified 67 active ingredients, 211 drug target proteins, 1539 disease targets, 105 shared targets, and 188 signaling pathways associated with WFC. WFC impacted cell apoptosis, proliferation, and the inflammatory response, with top tumor-related signaling pathways involving 5'-adenosine monophosphate-activated protein kinase (AMPK), mitogen-activated protein kinase, nuclear factor kappa-B (NFKB), and apoptosis. In vitro, WFC inhibited proliferation and migration while inducing apoptosis in GC cells, reduced VEGFA, TNFa, and IL6 expressions. Immunocytochemistry showed increased p-AMPK staining, and molecular analysis revealed decreased NFKB and phosphorylation of extracellular-regulated protein kinase 1/2 (ERK1/2) levels, increased p-AMPK and BAX protein levels in WFC-treated cells, effects reversed by Compound C. WFC's antitumor effects involve AMPK-dependent ERK1/2 and NFKB pathways, regulating proliferation, migration, and apoptosis in GC cells.

Oncogenic transcription factors instruct promoter-enhancer hubs in individual triple negative breast cancer cells.

Sequencing-based mapping of ensemble pairwise interactions among regulatory elements support the existence of topological assemblies known as promoter-enhancer hubs or cliques in cancer. Yet, prevalence, regulators, and functions of promoter-enhancer hubs in individual cancer cells remain unclear. Here, we systematically integrated functional genomics, transcription factor screening, and optical mapping of promoter-enhancer interactions to identify key promoter-enhancer hubs, examine heterogeneity of their assembly, determine their regulators, and elucidate their role in gene expression control in individual triple negative breast cancer (TNBC) cells. Optical mapping of individual SOX9 and MYC alleles revealed the existence of frequent multiway interactions among promoters and enhancers within spatial hubs. Our single-allele studies further demonstrated that lineage-determining SOX9 and signaling-dependent NOTCH1 transcription factors compact MYC and SOX9 hubs. Together, our findings suggest that promoter-enhancer hubs are dynamic and heterogeneous topological assemblies, which are controlled by oncogenic transcription factors and facilitate subtype-restricted gene expression in cancer.

Exploring the presence and persistence of cartographic anchors in pan-scalar maps

ABSTRACT Within this article, we hypothesize that, in the virtual space of pan-scalar maps, i.e. interactive, multi-scale and zoomable web maps, the map components perceived by the map user during a zoom can mimic the qualities of real-world anchors or landmarks to help self-localization in map. This article explores the characterizations of these potential cartographic anchors through the analysis of overlapping digital drawings on map views, collected with an online user survey. Our results allow us to identify possible cartographic anchors, characterize them in their variability, identify similar logics despite variations in localization, and discuss origins of these perceptual comparisons.

What are the methodological characteristics of evidence and gap maps? A systematic review and evidence and gap map

AbstractIntroductionClarity on the characteristics of methods used to produce evidence and gap maps (EGMs) will highlight areas where method development is needed to ensure these increasingly produced tools are made following best practice to assure their quality and utility. This paper aims to describe the range, nature and variability of key methodological characteristics of studies publishing EGMs.MethodsWe followed a protocol, written a‐prior and informed by PRISMA and MECCIR guidelines for undertaking systematic reviews. We searched nine data bases, from 2010, for studies across any discipline that included details of their methods used to produce an EGM. Search results were screened by two reviewers independently and the subsequent data was extracted and managed according to predefined criteria. We mapped these together with the year of publication and the area of research as the two primary dimensions. We followed established methods for mapping the evidence, including the process of developing the map framework and the filters for our interactive map. We sought input and involvement from stakeholders during this process.ResultsWe found 145 studies from nine distinct research areas, with health research accounting for 67%. There were 11 map designs found, of these bubble plots were the most common design, before 2019, since then it has been a matrix map design. Stakeholders were involved in 47.7% of studies, 48.35% of studies stated finding gaps was an aim of their work, 42% reported publishing or registering a protocol and only 9.39% of studies mentioned a plan to update their evidence maps/EGMs.Discussion/ConclusionKey areas of methodological development relate to: the involvement of stakeholders, the conceptualization of gaps and the practices for updating maps. The issues of ambiguity in terminology, the flexibility of visualizations of the data and the lack of reporting detail were other aspects that needs further consideration in studies producing an EGM.

Spatial 3D genome organization controls the activity of bivalent chromatin during human neurogenesis.

The nuclear genome is spatially organized into a three-dimensional (3D) architecture by physical association of large chromosomal domains with subnuclear compartments including the nuclear lamina at the radial periphery and nuclear speckles within the nucleoplasm1-5. However, how spatial genome architecture regulates human brain development has been overlooked owing to technical limitations. Here, we generate high-resolution maps of genomic interactions with the lamina and speckles in cells of the neurogenic lineage isolated from midgestational human cortex, uncovering an intimate association between subnuclear genome compartmentalization, chromatin state and transcription. During cortical neurogenesis, spatial genome organization is extensively remodeled, relocating hundreds of neuronal genes from the lamina to speckles including key neurodevelopmental genes bivalent for H3K27me3 and H3K4me3. At the lamina, bivalent genes have exceptionally low expression, and relocation to speckles enhances resolution of bivalent chromatin to H3K4me3 and increases transcription >7-fold. We further demonstrate that proximity to the nuclear periphery - not the presence of H3K27me3 - is the dominant factor in maintaining the lowly expressed, poised state of bivalent genes embedded in the lamina. In addition to uncovering a critical role of subnuclear genome compartmentalization in neurogenic transcriptional regulation, our results establish a new paradigm in which knowing the spatial location of a gene is necessary to understanding its epigenomic regulation.