Biology subjects

Liebig, J.

Publications and source records attributed to Liebig, J..

9 recordsLinked to original sources

bioRxiv2026

Evolution of SARS-CoV-2 reshapes upper airway immunity in children

Children were relatively protected from severe COVID-19 during the early pandemic a phenomenon linked to rapid and heightened innate immune responses in the upper-airways. Although adult upper-airway antiviral responses varied across successive SARS-CoV-2 waves, whether viral evolution similarly reshaped pediatric mucosal immunity remains unclear. Here we used single-cell transcriptomics to profile 229,533 upper-airway cells from 68 unvaccinated children including 17 uninfected controls, spanning the wild-type SARS-CoV-2, Alpha, Delta and Omicron waves. Epithelial interferon responses were primarily determined by time since symptom onset but were, unlike in adults, independent of disease severity. During early infection, anti-viral responses differed across variants without following a progressive pattern of attenuation. Alpha and Delta elicited the strongest interferon programs across epithelial and immune cell populations, whereas Omicron exhibited a shift towards macrophage cytokine signaling and T-cell cytotoxicity. These findings reveal variant-specific remodeling of pediatric upper-airway immunity that fundamentally differs from that described in adults.

immunology↗

bioRxiv2025

Latent plasticity of the human pancreas across development, health, and disease.

The pancreas plays a central role in major human diseases, yet our understanding of its cellular diversity and plasticity remains incomplete. Here, we present a single-cell multiomics atlas of the human pancreas, profiling over four million cells and nuclei from 57 donors across fetal development, adult homeostasis, and type 2 diabetes (T2D). Integrating sc/snRNA-seq, snATAC-seq, VASA-seq, spatial transcriptomics (Xenium), and multiplexed proteomics (CODEX), we resolve gene expression, chromatin accessibility, and spatial organization at high resolution. We identify transcriptionally plastic centroacinar-like cells (pCACs) in adults with fetal-like features, delineate endocrine and exocrine lineage trajectories during development, and uncover HNF1A-defined beta cell epigenetic states. In T2D, we observe shifts in beta cell subtypes and altered regulatory programs. Glucose perturbation of healthy islets reveals cell-type-specific adaptation and stress responses. This atlas provides a foundational framework to understand pancreas biology and the role of cellular plasticity in regeneration and disease.

genomics↗

bioRxiv2024

Tbx1 stabilizes differentiation of the cardiopharyngeal mesoderm and drives morphogenesis in the pharyngeal apparatus

BackgroundTBX1 is required for the development of the pharyngeal apparatus. In the mouse, fish, and ascidian, Tbx1 is a marker of cardiopharyngeal mesoderm (CPM), a cell population that provides progenitors to the heart and branchiomeric muscles. However, in mammals: a) the molecular cascade that drives the diversification of this multipotent cell population, and b) the role of Tbx1 therein, are not well defined. Material and methodsWe used in vitro differentiation of WT and Tbx1-/- mouse embryonic stem cells into precardiac mesoderm, and performed single cell RNA-seq and ATAC-seq at two differentiation stages. We then used WT and Tbx1-/- mouse embryos for in vivo validation of the key findings. Results and conclusionsWe found that the response to loss of TBX1 is cell sub-population-specific, both in terms of gene expression and chromatin remodeling. We show that Tbx1 regulates chromatin accessibility and gene expression of an ancient transcriptional module that orchestrates the development of the trunk, pharynx and heart across evolution. This module is co-regulated and includes genes encoding the conserved transcription factor families of Tea Shirt (Tshz), Sine Oculis (Six), Eye absent (Eya), and Ebf/Collier. Analysis of putative regulatory regions of these genes, which were selected using a machine-learning computational procedure, predicted a feed-forward regulatory relationship between TBX1 and SIX factors that drives or stabilizes the module. Most surprisingly, we found a drift in the differentiation trajectory of the Tbx1 mutant CPM that led to a relative expansion of cells with epithelial-like transcriptional features in the cell culture model and in mouse embryos. We conclude that TBX1 is a critical factor for maintaining the transcriptional profile of the CPM.

developmental biology↗

bioRxiv2024

Population dynamics after pancreatitis dictates long-lasting epigenetic reprogramming and mediates tumor predisposition

Local inflammation in the pancreas is transient but imprints a durable epigenetic memory on epithelial cells, making them more amenable to oncogenic transformation. However, it is unclear whether epithelial cell heterogeneity is impacted by acute pancreatitis (AP) or whether population dynamics during regeneration contributes to the establishment of inflammation memory. To tackle those questions, we deployed experimental pancreatitis in mice and performed paired sequencing of transcriptomic and chromatin accessibility profiles at single nucleus resolution. We documented cell type abundance but also applied integrative analyses to infer phenotypically-distinct clusters of mesenchymal and exocrine cells. We found that AP perturbs a subset of "idling" acinar cells, which separate from more canonical "secretory" acini based on a more diversified proteome, which include elevated expression of signal transduction receptors. We linked acinar cell heterogeneity to epigenetic differences that also endow idling cells with superior plasticity. These constitute about 40% of acinar cells but can proliferate and skew their phenotype in response to AP. This leads to a remarkable recovery of pancreas histology and function, but also to the dissemination of idling-like features across the exocrine parenchyma. Mechanistically, idling acinar cells are characterized by enhanced transcriptional activity and protein synthesis. After recovery from pancreatitis, acini show elevation of both and establishment of chronic Unfolded Protein Response (UPR). We finally demonstrated that AP-primed pancreata show signs of elevated UPR and that ER stress promotes acinar cell metaplasia. Our data interrogate phenotypical dynamics during tissue regeneration to identify cell states amenable to epigenetic imprinting. They also suggest that UPR-alleviating strategies might curtail the risk of developing pancreatic cancer for individuals who experiences AP.

cell biology↗

bioRxiv2024

Inferring a role for programmed cell death during the origin and evolution of wing polyphenism in ants

Major evolutionary transitions in individuality occur when solitary individuals unite to form a single replicating organism with a division of labor between constituent individuals. Key examples include the evolution of multicellularity, eusociality, and obligate endosymbiosis. Programmed Cell Death (PCD) has been proposed to play an important role during major transitions to multicellularity, yet it remains unclear to what extent PCD plays a role in other major transitions. Here we test if PCD was involved in the major transition to eusociality in ants, where solitary individuals united to form eusocial colonies with a division of labor between a winged queen caste and a wingless worker caste. The development of wings in queens but not in workers in response to environmental cues is called wing polyphenism, which evolved once and is a general feature of ants. Both wing polyphenism and eusociality evolved at the same time during the origin of ants and were likely intimately linked--the suppression of wings in workers may have reduced their ability to participate in mating flights thereby reinforcing the reproductive division of labor within the parental nest. We therefore tested whether PCD plays a role in the degeneration of wings during development of the worker caste across the ant phylogeny encompassing species with both ancestral-like and derived characteristics. We show that PCD, mediated by the apoptosis pathway, is present in the degenerating wing primordia of worker larvae in 15 out of the 16 species tested. Using ancestral state reconstruction, we infer a role for PCD in regulating wing polyphenism in the last common ancestor of all extant ants. Our findings provide evidence that a degenerative mechanism (PCD) plays a role in the origin of wing polyphenism, and therefore, in facilitating the major transition to eusociality in ants. PCD may generally play a key role in the evolution of biological complexity by facilitating major transitions at different scales, such as multicellularity and eusociality.

evolutionary biology↗

bioRxiv2022

Transcriptionally defined morphological subtypes of pancreatic ductal adenocarcinoma

Tumour heterogeneity remains a major obstacle to effective and precise therapy for pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer. Several transcriptional subtypes of PDAC with differential prognosis have been described, but they co-occur within tumours and are difficult to distinguish in routine clinical workflows. To investigate the relationship between transcriptional PDAC subtypes, local tissue morphology and the tumour microenvironment, we employed in situ sequencing to profile single cells in their spatial tissue context. We identify five transcriptional subtypes of PDAC cells occurring in three distinct morphological patterns, including secretory tumour cell monolayers, invasive tumour cells with high expression of cell adhesion molecules CEACAM5 and CEACAM6, and spatially distributed tumour cells associated with inflammatory-type fibroblasts. Analysis of bulk RNA-sequencing datasets of the TCGA-PAAD and PACA-AU cohorts according to these spatio-transcriptional subtypes confirmed their prognostic significance. Our results thus indicate an automatable substratification based on spatially-resolved transcriptomics of PDAC and identify distinct subtypes of classical PDAC, representing most cases of this devastating malignancy.

cancer biology↗

bioRxiv2021

Genetic and genomic architecture of species-specific cuticular hydrocarbon variation in parasitoid wasps

Cuticular hydrocarbons (CHCs) serve two fundamental functions in insects: protection against desiccation and chemical signaling. CHC profiles can consist of dozens of different compounds and are considered a prime example for a complex trait. How the interaction of genes shapes CHC profiles, which are essential for insect survival, adaptation, and reproductive success, is still poorly understood. Here we investigate the genetic and genomic basis of CHC biosynthesis and variation in parasitoid wasps of the genus Nasonia. Taking advantage of the wasps haplo-diploid sex determination and cross-species fertility, we mapped 91 quantitative trait loci (QTL) explaining variation of a total of 43 CHCs in F2 hybrid males from interspecific crosses between three Nasonia species. To identify candidate genes, we localized orthologs of CHC biosynthesis-related genes in the Nasonia genomes. By doing so, we discovered multiple genomic regions where the location of QTL coincides with the location of CHC biosynthesis-related candidate genes. Most conspicuously, on a region on chromosome 1 close to the centromere, multiple CHC biosynthesis-related candidate genes co-localize with several QTL explaining variation in methyl-branched alkanes. The genetic underpinnings behind this compound class are not well understood so far, despite their high potential for encoding chemical information as well as their prevalence in both Nasonia CHC profiles and many other Hymenoptera. Our study considerably extends our knowledge on the so far little-known genetic and genomic architecture governing biosynthesis and variation of this fundamental compound class, establishing a model for methyl-branched alkane genetics in the Hymenoptera in general.

genetics↗

bioRxiv2021

Loss of wings induces the expression of the worker-like phenotype in queens of a ponerine ant

Many highly-eusocial insect species are characterized by morphological differences between females. This is especially pronounced in ants where queens usually possess a fully developed thorax with wings and are specialized for reproduction while workers have a reduced thorax without wings and show various levels of reproductive degeneration that is associated with their helper role in the colony. Despite their morphological differentiation, queens and workers still show some plasticity leading to overlapping behavioral and physiological phenotypes. We investigated the level of queen plasticity and the factor that induces a worker-like phenotype in the ant species Harpegnathos saltator that has limited queen-worker dimorphism and workers that can assume the reproductive role of a queen in the colony. By comparing alate and dealate young queens, so-called gynes, we found that the loss of wings initiated the expression of behavioral and physiological characteristics of ant workers. In contrast to alate gynes, dealate gynes displayed higher frequencies of worker-like behaviors. In addition, dealate gynes showed a worker-like range of reproductive states unlike alate gynes. Like workers, dealate gynes lost the chemical signaling that is characteristic of alate gynes. Since gynes can activate this worker-like phenotype after wing loss, the essential difference between the ant queens and workers in this species with limited queen-worker dimorphism is a dispersal polyphenism. If the phenotypic plasticity observed in H. saltator is representative of the early stages of ant eusociality, an emerging dispersal dimorphism rather than a distinct reproductive dimorphism might represent one of the first steps in ant evolution. Summary StatementAnt queens who have lost their wings express worker-like behaviors and physiology including the display of dominance behavior during hierarchy establishment, which is normally a worker-only behavior in this species.

animal behavior and cognition↗

bioRxiv2017

Olfactory Receptors Are Required For Social Behavior And Neural Plasticity In Ants, As Evidenced By CRISPR-Mediated Gene Knockout

The chemosensory system is key to establishing and maintaining social structure in eusocial insects. Ants exhibit cooperative colonial behaviors reflective of an advanced form of sociality with an extensive dependency on communication. Cuticular hydrocarbons (CHCs) serve as pheromones and cues that regulate multiple aspects of social interactions and behaviors in ants. The perception of CHCs entails odorant receptor neurons (ORNs) that express specific odorant receptors (ORs) encoded by a dramatically expanded Or gene family in ants. Until recently, studies of the biological functions of ORs in eusocial insects were stymied by the lack of genetic tools. In most eusocial insect species, only one or a few queens in a colony can transmit the genetic information to their progeny. In contrast, any worker in the ant Harpegnathos saltator can be converted into a gamergate (pseudo-queen), and used as a foundress to engender an entire new colony and be crossed for genetic experiments. This feature facilitated CRISPR-Cas9 gene targeting to generate a germline mutation in the orco gene that encodes the obligate co-receptor whose mutation should significantly impact ant olfaction. Our results show that Orco exhibits a conserved role in the perception of general odorants but also a role in reproductive physiology and social behavior plasticity in ants. Surprisingly, and in contrast to other insect systems, the loss of OR functionality also dramatically reduces the development of the ant antennal lobe where ORNs project. Taken together, these findings open the possibility of studying the genetics of eusociality and provide inroads towards understanding the function of the expanded ORs family in eusocial insects in regulating caste determination, social communication and neuronal plasticity.

neuroscience↗