Biology subjects

Mead, A.

Publications and source records attributed to Mead, A..

17 recordsLinked to original sources

bioRxiv2026

Genetic variation underlying plasticity in physiological traits mediates response to climate in a Populus hybrid zone

Phenotypic plasticity can buffer the potential fitness consequences of environmental change, yet limited understanding of its genetic basis constrains its application to predicting population response to future climates. Hybrid zones provide powerful systems to study the genetic basis of plasticity because admixture can create novel allele combinations that generate new reaction norms for selection to act upon. Here, we combine two clonally replicated common gardens of Populus trichocarpa x P. balsamifera genotypes with whole-genome resequencing to identify genetic variation underlying plasticity for physiological traits. Admixed genotypes exhibited broader, and in some cases novel, reaction norms relative to parental genotypes, particularly for key stomatal traits. Admixture mapping of genotype-specific reaction norms identified ten candidate genes on chromosome 15, including TWIST, associated with plasticity in adaxial stomatal occurrence and density. Using random forest models, we projected allele-specific responses to climate warming within the hybrid zone to link genetic variation in plasticity with predicted warming. Random forest models forecast that future climates would favor P. trichocarpa alleles at TWIST, while P. balsamifera alleles would be maintained in heterozygous genotypes. These results suggest that hybridization can expand reaction norms and maintain genetic variation that may facilitate rapid phenotypic response needed to adapt to climate change.

evolutionary biology↗

bioRxiv2026

Phenotypic plasticity evolved for climate variability constrains performance under climate warming

Phenotypic plasticity allows plants to rapidly respond to changing environments without the need for evolutionary change or migration. While selection can create variation in plasticity across natural populations, these responses are not adaptive in all environments. To predict whether plasticity will be adaptive requires evaluation of its fitness effects across a range of environments, including novel ones. Here, we test how traits and their plasticity vary for genotypes collected across a natural hybrid zone between two tree species with contrasting climatic niches. Fast-growing Populus trichocarpa inhabits maritime environments with relatively warm and stable temperatures, while P. balsamifera inhabits continental environments with cold winters and large temperature variance throughout the year. We planted 44 clonally replicated genotypes into thirteen common gardens and measured vegetative phenology, leaf morphology, stomata morphology and conductance, and photochemistry. Overall, genotypes from colder, more continental environments exhibited higher plasticity. P. balsamifera ancestry was associated with increased plasticity in timing of fall phenology, stomatal conductance, and leaf mass per unit area. We assessed the effects of trait plasticity on fitness estimated as yearly growth across common gardens and found that the plasticity-fitness relationship was often garden-specific, indicating that the planting environment did not consistently mediate plasticity-fitness relationships. When the effects of trait plasticity on growth varied by garden temperature, higher plasticity generally had neutral or negative associations with growth in warmer environments. These results suggest that elevated plasticity evolved in a P. balsamifera genomic background as part of a climate generalist strategy to seasonal temperature variability, but that there is a trade-off between plasticity and growth in warmer environments. Consequently, less-plastic but warm-adapted P. trichocarpa genotypes are likely to have a fitness advantage under warming climates. These results demonstrate that plasticity may sometimes be maladaptive and will not be universally beneficial in a warming world.

evolutionary biology↗

bioRxiv2026

CAR T cell therapy selectively depletes disease-driving mutant calreticulin cells in xenotransplants and human organoid models of myelofibrosis

Targeted immunotherapies have revolutionized outcomes for lymphoid malignancies, but success in myeloid neoplasms is limited by the lack of amenable targets and immunologically hostile tumor microenvironment (TME). Myeloproliferative neoplasms are chronic myeloid blood cancers, a third of which are driven by mutations in calreticulin (mutCALR). This yields a common neoepitope that binds to, and activates, the thrombopoietin receptor and results in display of the oncoprotein on the extracellular membrane of disease-driving cells, exposing a therapeutic vulnerability. Here, we present a first-in-class chimeric antigen receptor (CAR) T-cell therapy that specifically targets mutCALR+ cells, both in vitro and in vivo. The CAR T-cell therapy selectively depleted mutCALR+ stem cells from patients with myelofibrosis while sparing healthy stem cells, and improved survival in mutCALR leukemia xenografts. To mimic myelofibrotic marrow, we developed a bespoke human chimeroid model and showed no decrease in the potency of CAR T cell-mediated target cell killing even in a fibrotic tumor microenvironment. We also devised a method to boost cell surface expression of mutCALR in CD34+ cells isolated from patients with accelerated/blast phase MPN (defined as >10 % blasts in peripheral blood or bone marrow), enhancing CAR T targeting. This study presents a therapeutic with potential to eradicate mutCALR-driven malignancies and highlights an innovative strategy to evaluate blood cancer-targeting immunotherapies in a relevant TME. One Sentence SummaryA first-in-class CAR T-cell therapy targeting mutant calreticulin selectively depletes malignant stem cells in vivo and in fibrotic human organoids.

cancer biology↗

bioRxiv2025

Redefining the topology of the human bone marrow using augmented spatial transcriptomic analysis

The bone marrow (BM) is the main site of haematopoiesis in adult life. Our understanding of the pathogenesis of BM-derived blood cancers is limited by lack of spatial contextualisation. While emerging spatial transcriptomic (ST) platforms offer unprecedented opportunities for spatially-resolved cellular phenotyping, we recognise and incorporate the power of AI-based tissue feature detection to enhance ST workflows. We perform ST analysis to define the topology of the normal bone marrow (BM) and BM in myeloproliferative neoplasms (MPNs), profiling 5,104,452 cells across 30 human BM samples. Following rigorous histology-based QC, we identify spatially-restricted trajectories of haematopoiesis and extend our understanding of the haematopoietic stem cell (HSC) niche. We find that BM fibrosis in MPN is associated with expansion of distinct immune and stromal co-enriched cell neighbourhoods. We then present a machine learning (ML)-based model trained on ST data that quantifies BM microenvironmental deviation, identifying heretofore unrecognised inter- and intra-individual sample heterogeneity in MPN. Our study demonstrates the potential for AI-based augmented ST analysis, and redefines our understanding of human BM topology.

cancer biology↗

bioRxiv2025

Drought tolerance is associated with constitutive gene expression, not plasticity, across California oak species

O_LIDrought is a major stressor for plants globally. Variation in gene expression patterns across species can provide critical evidence for the genomic basis of drought tolerance. C_LIO_LIWe paired comparative transcriptomics with functional trait measurements to identify genomic mechanisms associated with drought tolerance across six species from three oak clades in California, including a pair of species within each clade representing relatively mesic or xeric environments. We tested how plastic and constitutive gene expression patterns varied among species with contrasting drought tolerance traits. We also tested whether gene expression responses were decoupled from phylogenetic history, suggesting they have evolved multiple times as adaptations to species climate niches. C_LIO_LISpecies with drought-tolerant traits exhibited lower levels of gene expression plasticity during leaf dehydration than drought-sensitive species, but showed signatures of positive selection on constitutive gene expression. Drought-sensitive species across clades converged in their patterns of plastic gene expression during dehydration, diverging from their more closely related drought tolerant species, suggesting that repeated evolution has shaped plastic gene expression responses to drought. C_LIO_LIDrought-tolerant oak species have evolved constitutive gene expression alongside drought tolerant functional traits, while drought-sensitive oak species have evolved similar plastic gene expression responses to drought. C_LI

evolutionary biology↗

bioRxiv2025

Variation in responses to temperature across admixed genotypes of Populus trichocarpa x P. balsamifera predict geographic shifts in regions where hybrids are favored

O_LIPlastic responses of plants to their environment vary as a result of genetic differentiation within and among species. To accurately predict rangewide responses to climate change, it is necessary to characterize genotype-specific reaction norms across the continuum of historic and future climate conditions comprising a species range. C_LIO_LIThe North American hybrid zone of Populus trichocarpa and P. balsamifera represents a natural system that has been shaped by climate, geography, and introgression. We leverage a dataset containing 45 clonal genotypes from this natural hybrid zone, planted across 17 replicated common garden experiments spanning a broad climatic range. Growth and mortality were measured over two years, enabling us to model reaction norms for each genotype across these tested environments. C_LIO_LISpecies ancestry and intraspecific genomic variation significantly influenced growth across environments, with genotypic variation in reaction norms reflecting a trade-off between cold tolerance and growth. Using modeled reaction norms for each genotype, we predicted that genotypes with more P. trichocarpa ancestry may gain an advantage under warmer climates. C_LIO_LISpatial shifts of the hybrid zone could facilitate the spread of beneficial alleles into novel climates. These results highlight that genotypic variation in responses to temperature will have landscape-level effects. C_LI

evolutionary biology↗

bioRxiv2024

Quantifying relative sponginess: a high-resolution model of landscape water retention as an ecosystem service

Unprecedented climate and land use changes are having major impacts on water-based ecosystem services (ES). It is crucial, therefore, to get an in-depth understanding of current levels of such ES provision, and how they could be impacted by changed environments or management. However, applying existing models for water-related ES pose substantial challenges, which include the need for in-depth specialist hydrological knowledge, the requirement for numerous datasets and parameters that may not be consistently available, and high computational costs. Additionally, there is often a mismatch between the resolution of the model output and parcel-level land management, at which ES information is often most valuable for supporting decision-making. Here we detail a rapid method for assessing water retention potential by estimating an areas sponginess - its capacity to absorb and retain precipitation. Our approach builds upon a topography-adjusted Curve Number methodology, a widely recognised and straightforward tool for estimating water run-off. We calculated run-off across 1 km grid cells (representing field- to farm-scale land parcels) in Great Britain based on the lands sponginess under storm conditions. The primary objective was to investigate the applicability of the method in estimating point-values -- i.e., the independent contribution of each grid square -- within the context of known limitations. The results enable the identification of areas with higher potential for the ES of water retention. Our model output illustrates the spectrum of sponginess across Great Britain, ranging from less than 30% of precipitation retained in city regions to as high as 99% in some rural, agricultural areas. Importantly, we demonstrate that the model is easy to run, can be used with freely-available data, and produces outputs compatible with grid-based models for other ES. Overall, the model provides an accessible approach to estimating the ES of water retention to researchers worldwide, even in data-scarce areas. Highlights- To inform land management decisions it is important to determine parcel-level ecosystem services, but there is a gap for services related to water. - Parcel-level assessments of a lands sponginess - the capacity to retain precipitation - are described. - Values are calculated using a topography-adjusted Curve Number methodology, which requires little data input or hydrological expertise. - Sponginess and run-off estimates are provided for Great Britain at 1 km resolution.

ecology↗

bioRxiv2024

Robust CRISPR/dCas13 RNA blockers specifically perturb miRNA-target interactions and rescue type 1 myotonic dystrophy pathology

While RNA-targeting strategies are powerful tools for disease therapy, challenges, including low target engagement and off-target collateral effects, currently limit their efficacy. Here, we report the engineering and optimisation of a CRISPR/dCas13 RNA steric blocker (CRISPR-Lock) that prevents mRNA translation, shields mRNAs from miRNA-mediated silencing, and blocks RNA-protein interactions. By tuning the spatial resolution and mismatch tolerance of CRISPR-Lock, we develop a high-resolution perturbation approach that employs genetically encoded CRISPR-Lock as a miRNA target protector. This system enables precise spatiotemporal control of miRNA:mRNA interactions, offering broader applicability compared to phosphorodiamidate mor-pholino (PMO) target protectors. Moreover, we demonstrate the potential therapeutic application of CRISPR-Lock for blocking pathological RNA-protein interactions in type 1 myotonic dystro-phy (DM1). Optimising CRISPR-Lock to target expanded repeat RNAs corrects approximately 85% of clinically relevant splicing biomarkers in patient-derived myotubes and significantly out-performs third-generation PMO antisense oligonucleotides. Finally, by delivering a miniaturised AAV-encoded CRISPR-Lock system into an established DM1 mouse model, we demonstrate the dose-dependent correction of intranuclear foci and splicing dysregulation, underscoring the potential therapeutic application of this technology.

bioengineering↗

bioRxiv2024

Sensitivities in associating land-system archetypes with sustainability metrics: Insights from simulations

Archetypes of land- and socio-ecological systems, generated using unsupervised classification methods, enable the assimilation of complex environmental and socio-economic information. Such simplification has considerable potential to feed into decision support systems for sustainability planning. But, the usefulness of archetypes depends on how well they relate to sustainability criteria, such as ecosystem service (ES) delivery, that are external to the input datasets employed for archetype generation. Sensitivities in such post-hoc association analyses, and the associated utility of the archetype framework in a decision support context, remain unexplored. Here we emulated post-hoc association analysis procedures using simulated socio-ecological datasets and ES response variables. Our simulations revealed a substantial influence on analysis performance from (1) the number of variables used as inputs in archetype generation, (2) the correlation structure of input datasets, (3) the type and distribution of input variables, and (4) the functional form (linear or non-linear) characterising the relationship between ES variables and their predictors. We observed near-identical performance when archetypes were generated using K-means clustering and Self-Organising Maps (SOMs) - two commonly used archetype classification methods. Further, better archetype classifier performance did not guarantee better discrimination of ES value distributions between archetypes. Our results suggest that designing a framework to generate archetypes for sustainability planning, and the selected methodological choices therein, should place greater emphasis on what the archetypes will be used for in downstream analyses, and not focus solely on archetype classifier performance. This would better ensure the identification of archetypes adaptable to a diverse array of sustainability indicators and sufficiently robust for monitoring decision outcomes over time.

ecology↗

bioRxiv2024

Comparison of conservation strategies for California Channel Island Oak (Quercus tomentella) using climate suitability predicted from genomic data

Management strategies, such as assisted gene flow, could increase resilience to climate change in tree populations. Knowledge of evolutionary history and genetic structure of species is needed to assess the risks and benefits of different strategies. Quercus tomentella, or Island Oak, is a rare oak restricted to six Channel Islands in California, USA, and Baja California, Mexico. Previous work has shown that Island Oaks on each island are genetically differentiated, but it is unclear whether assisted gene flow could enable populations to tolerate future climates. We performed whole-genome sequencing on Island Oak individuals and Q. chrysolepis, a closely related species that hybridizes with Island Oak (127 total), to characterize genetic structure and introgression across its range and assess the relationship between genomic variation and climate. We introduce and assess three potential management strategies with different trade-offs between conserving historic genetic structure and enabling populations to survive changing climates: the status quo approach; ecosystem preservation approach, which conserves the trees and their associated biodiversity; and species preservation approach, which conserves the species. We compare the impact of these approaches on predicted maladaptation to climate using Gradient Forest. We also introduce a climate suitability index to identify optimal pairs of seed sources and planting sites for approaches involving assisted gene flow. We found one island (Santa Rosa) that could benefit from the ecosystem preservation approach and also serve as a species preservation site. Overall, we find that both the ecosystem and species preservation approaches will do better than the status quo approach. If preserving Island Oak ecosystems is the goal, assisted migration into multiple sites could produce adapted populations. If the goal is to preserve a species, the Santa Rosa population would be suitable. This case study both illustrates viable conservation strategies for Island Oak and introduces a framework for tree conservation.

evolutionary biology↗

bioRxiv2024

Genomic signature of reproductive isolation between the last two remnant populations of Torrey pine (Pinus torreyana Parry)

Tree species are often locally adapted to their environments, but the extent to which environmental adaptation contributes to incipient speciation is unclear. One of the rarest pines in the world, Torrey Pine (Pinus torreyana Parry), persists naturally across one island and one mainland population in southern California. The two populations are morphologically and genetically differentiated, but experience some connectivity, making it an ideal system for assessing the evolution of reproductive isolation. Previous work has found evidence of heterosis in F1 mainland-island hybrids, suggesting genetic rescue could be beneficial in the absence of reproductive barriers. Using ddRADseq and GWAS for a common garden experiment of island, mainland, and F1 individuals, we identified candidate loci for environmentally-driven reproductive isolation, their function, and their relationship to fitness proxies. By simulating neutral evolution and admixture between the two populations, we identified loci that exhibited reduced heterozygosity in the F1s, evidence of selection against admixture. SNPs with reduced F1 heterozygosity were enriched for growth and pollination functions, suggesting genetic variants that could be involved in the evolution of reproductive barriers between populations. One locus with reduced F1 heterozygosity exhibited strong associations with growth and reproductive fitness proxies in the common garden, with the mainland allele conferring increased fitness. If this locus experiences divergent selection in the two natural populations, it could promote their reproductive isolation. Finally, although hybridization largely reduced allele fixation in the F1s initially, indicating heterosis is likely due to the masking of deleterious alleles, the emergence of reproductive isolation between populations may diminish the longer-term benefits of genetic rescue in F2 or advanced-generation hybrids. As Torrey pine is a candidate for interpopulation genetic rescue, caution is warranted where longer-term gene flow between diverged populations may result in reduced fitness if barriers have evolved.

genomics↗

bioRxiv2023

A pro-inflammatory stem cell niche drives myelofibrosis through a targetable galectin 1 axis

Myeloproliferative neoplasms are stem cell-driven cancers associated with a large burden of morbidity and mortality. The majority of patients present with early-stage disease, but a substantial proportion progress to myelofibrosis and/or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and we lack therapies that reliably prevent or reverse fibrosis development. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the crosstalk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a quartet of immune and stromal cell lineages - with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells and pro-inflammatory fibroblasts. We identified the y-galactoside binding protein galectin 1 as a striking biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts, and as a promising therapeutic target, with reduced myeloproliferation and fibrosis in vitro and in vivo and improved survival following galectin 1 inhibition. In human bone marrow organoids, TNF increased galectin 1 expression, suggesting a feedback loop wherein the pro-inflammatory MPN clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a valuable resource for studying hematopoietic cell-niche interactions, with broad relevance for cancer-associated inflammation and disorders of tissue fibrosis.

cancer biology↗

bioRxiv2020

Time series transcriptomics reveals a BBX32-directed control of dynamic acclimation to high light in mature Arabidopsis leaves

The photosynthetic capacity of mature leaves increases after several days exposure to constant or intermittent episodes of high light (HL) and is manifested primarily as changes in chloroplast physiology. This is termed dynamic acclimation but how it is initiated and controlled is unknown. From fully expanded Arabidopsis leaves, we determined HL-dependent changes in transcript abundance of 3844 genes in a 0-6h time-series transcriptomics experiment. It was hypothesised that among such genes were those that contribute to the initiation of dynamic acclimation. By focussing on HL differentially expressed transcription (co-)factor (TF) genes and applying dynamic statistical modelling to the temporal transcriptomics data, a gene regulatory network (GRN) of 47 predominantly photoreceptor-regulated (co)-TF genes was inferred. The most connected gene in this network was B-BOX DOMAIN CONTAINING PROTEIN32 (BBX32). Plants over-expressing BBX32 were strongly impaired in dynamic acclimation and displayed perturbed expression of genes involved in its initiation. These observations led to demonstrating that as well as regulation of dynamic acclimation by BBX32, CRYPTOCHROME1, LONG HYPOCOTYL5, CONSTITUTIVELY PHOTOMORPHOGENIC1 and SUPPRESSOR OF PHYA-105 are also important regulators of this process. Additionally, the BBX32-centric GRN provides a view of the transcriptional control of dynamic acclimation distinct from other photoreceptor-regulated processes, such as seedling photomorphogenesis.

plant biology↗

bioRxiv2020

Impact of trimethoprim on the river microbiome and antimicrobial resistance.

Recent evidence suggests that anthropogenic activity can increase the levels of antimicrobial resistance (AMR) in the environment. Rivers and waterways are significant examples of environmental settings that have become repositories of antibiotics and antibiotic resistance genes (ARGs). Our recent study quantified drug concentrations in freshwater samples taken at a range of sites located on the Thames catchment; the highest levels of antibiotics and other drugs were recorded downstream of waste water treatment plants (WWTPs). One specific antibiotic: Trimethoprim (TMP) was shown at elevated concentrations reaching 2000ng/L at particular sites. We have also shown a correlative relationship between the residue of TMP and the prevalence of sulfonamide antibiotic resistance genes such as sul1. Despite this, there is still no evidence of a causative relationship between TMP concentrations and the prevalence of the ARGs at river sites. The aim of the current study was to conduct in-depth analysis using a combination of large metagenomic, geospatial and chemical datasets, in order to conduct a comparison between those sites with the highest TMP and lowest TMP levels across the Thames catchment. We aimed to establish the proximity of these sites to WWTPs, their population equivalence (PE) and land coverage. A secondary aim was to investigate seasonal variation in TMP and ARGs. Exploring these factors will help to decipher the clinical relevance of ARG accumulation at river sites. A significant correlation was shown between TMP levels at river sites and their distance downstream from a WWTP. Three sites located on the Rivers Cut and Ray showed significantly higher TMP concentrations in winter compared to summer. The population equivalence (PE) for sites with the highest TMP levels was significantly higher than those with the lowest levels. The land coverage of sites with the highest TMP levels was significantly more urban/suburban than sites with the lowest TMP concentrations, which were found to be significantly more arable. Five ARGs relevant to TMP and sulfonamides were identified across the Thames catchment. The most prevalent ARG was sul1, which was significantly more prevalent in winter compared to summer. By contrast sul2 was found to be significantly more prevalent in summer compared to winter at a site on the River Coln. The prevalence of the class 1 integron marker gene (inti1) did not differ significantly by season or between sites with the highest/lowest TMP levels.

microbiology↗

bioRxiv2019

Improving the diagnosis and classification of Ph-negative myeloproliferative neoplasms through deep phenotyping

Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by excessive proliferation of myeloid lineages. Accurate classification and appropriate management of MPNs requires integration of clinical, morphological and genetic findings. Despite major advances in understanding the molecular and genetic basis, morphological assessment of the bone marrow trephine (BMT) remains paramount in differentiating between MPN subtypes and reactive conditions. However, morphological assessment is heavily constrained by a reliance on subjective, qualitative and poorly reproducible criteria. To address this, we have developed a machine-learning strategy for the automated identification and quantitative analysis of megakaryocyte morphology using clinical BMT samples. Using a sample cohort of recently diagnosed or established ET (n = 48) and reactive control cases (n = 42) we demonstrated a high predictive accuracy (AUC = 0.95) of automated tissue ET diagnosis based upon these specific megakaryocyte phenotypes. These separate morphological phenotypes showed evidence of specific genotype associations, which offers promise that an automated cell phenotyping approach may be of clinical diagnostic utility as an adjunct to standard genetic and molecular tests. This has great potential to assist in the routine assessment of newly diagnosed or suspected MPN patients and those undergoing treatment / clinical follow-up. The extraction of quantitative morphological data from BMT sections will also have value in the assessment of new therapeutic strategies directed towards the bone marrow microenvironment and can provide clinicians and researchers with objective, quantitative data without significant demands upon current routine specimen workflows.

pathology↗

bioRxiv2019

Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia

Juvenile Myelomonocytic Leukemia (JMML) is a poor prognosis childhood leukemia usually caused by germline or somatic RAS-activating mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA-sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin-CD34+CD38-CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment with RAS-activating mutations as a \"first hit\", (2) mutations are acquired with both linear and branching patterns of clonal evolution and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal inter-patient heterogeneity of JMML-LSCs which are present in, but not confined to, the phenotypic HSC compartment. RNA-sequencing of JMML-LSCs reveals upregulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, CD96) paving the way for LSC-directed disease monitoring and therapy in this disease.

cancer biology↗

bioRxiv2017

From pioneer to repressor: Bimodal foxd3 activity dynamically remodels neural crest regulatory landscape in vivo

The neural crest (NC) is a transient embryonic stem cell population characterised by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of foxd3-mutant versus wild type cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by foxd3 biotin-ChIP and single cell profiles of foxd3-expressing premigratory NC, our analysis shows that during early steps of NC formation, foxd3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffing nucleosomes. Strikingly, foxd3 then switches from an activator to its canonical role as a transcriptional repressor. Taken together, these results demonstrate that foxd3 acts bimodally in the neural crest as a switch from permissive to repressive nucleosome/chromatin organisation to maintain stemness and define cell fates.

developmental biology↗