Biology subjects

Roels, J.

Publications and source records attributed to Roels, J..

11 recordsLinked to original sources

bioRxiv2025

Stress attenuation by the adrenergic-specific lncRNA NESPR prevents cell death in neuroblastoma cells

Neuroblastoma is a pediatric cancer of the sympathetic nervous system characterized by heterogeneous cell states that mirror normal differentiation trajectories. Each state is governed by a core regulatory transcriptional circuitry that reinforces cell identity through an autoregulatory feedforward loop. We identified the long non-coding RNA NESPR as specifically expressed in adrenergic neuroblastoma cells. NESPR expression correlates with high-risk neuroblastoma clinical parameters and poor patient survival. NESPR is located within an insulated gene neighborhood alongside PHOX2B, a master transcription factor of the adrenergic identity. NESPR depletion reduced cell proliferation and increased caspase activity in neuroblastoma cell lines, and NESPR knockout in a neuroblastoma zebrafish model led to reduced tumor penetrance. Subcellular localization revealed NESPR to be a cytosolic long non-coding RNA, suggesting a trans-regulatory function. RNA-sequencing following NESPR depletion revealed a shift from an adrenergic to a mesenchymal cell state, due to proteotoxic stress-induced molecular reprogramming. These findings suggest NESPR as a regulator of neuroblastoma cell identity with potential therapeutic opportunities in high-risk neuroblastoma cases.

genetics↗

bioRxiv2024

Focal Deletions of a Promoter Tether Activate the IRX3 Oncogene in T Cell Acute Lymphoblastic Leukemia

Oncogenes can be activated in cis through multiple mechanisms including enhancer hijacking events and noncoding mutations that create enhancers or promoters de novo. These paradigms have helped parse somatic variation of noncoding cancer genomes, thereby providing a rationale to identify noncanonical mechanisms of gene activation. Here we describe a novel mechanism of oncogene activation whereby focal copy number loss of an intronic element within the FTO gene leads to aberrant expression of IRX3, an oncogene in T cell acute lymphoblastic leukemia (T-ALL). Loss of this CTCF bound element downstream to IRX3 (+224 kb) leads to enhancer hijack of an upstream developmentally active super-enhancer of the CRNDE long noncoding RNA (-644 kb). Unexpectedly, the CRNDE super-enhancer interacts with the IRX3 promoter with no transcriptional output until it is untethered from the FTO intronic site. We propose that promoter tethering of oncogenes to inert regions of the genome is a previously unappreciated biological mechanism preventing tumorigenesis.

cancer biology↗

bioRxiv2023

S100A8-enriched microglia populate the brain of tau-seeded and accelerated aging mice

Long considered to fluctuate between pro- and anti-inflammatory states, it has now become evident that microglia occupy a variegated phenotypic landscape with relevance to aging and neurodegeneration. However, whether specific microglial subsets converge in or contribute to both processes that eventually affect brain function is less clear. To investigate this, we analyzed microglial heterogeneity in a tauopathy mouse model (K18-seeded P301L) and an accelerated aging model (senescence accelerated mouse prone 8, SAMP8) using cellular indexing of transcriptomes and epitopes by sequencing. We found that widespread tau pathology in K18-seeded P301L mice caused a significant change in the number and morphology of microglia, but only a mild overrepresentation of disease-associated microglia. At the cell population-level, we observed a marked upregulation of the calprotectin-encoding genes S100a8 and S100a9. In 9-months-old SAMP8 mice, we identified a unique microglial subpopulation that showed partial similarity with the disease-associated microglia phenotype and was additionally characterized by a high expression of the same calprotectin gene set. Immunostaining for S100A8 revealed that this population was enriched in the hippocampus, correlating with the cognitive impairment observed in this model. However, incomplete colocalization between their residence and markers of neuronal loss suggests regional specificity. Importantly, S100A8-positive microglia were also retrieved in brain biopsies of human AD and tauopathy patients as well as in a biopsy of an aged individual without reported pathology. Thus, the emergence of S100A8-positive microglia portrays a conspicuous commonality between accelerated aging and tauopathy progression, which may have relevance for ensuing brain dysfunction. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/566543v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@d1e4e1org.highwire.dtl.DTLVardef@98adeorg.highwire.dtl.DTLVardef@7c15aaorg.highwire.dtl.DTLVardef@7265ca_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

An autophagy program that promotes T cell egress from the lymph node controls responses to immune checkpoint blockade

Lymphatic endothelial cells (LECs) lining the lymphatic vessels of the lymph node (LN) parenchyma orchestrate leukocyte trafficking and peripheral T cell dynamics. T cell responses to immunotherapy largely rely on peripheral T cell recruitment in tumors. Yet, a systematic and molecular understanding of how LECs within the LNs control T cell dynamics under steady state and tumor-bearing conditions is lacking. Using intravital and high-resolution imaging combined with immune phenotyping, we show that LEC-specific deletion of the essential autophagy gene Atg5 alters intranodal positioning of lymphocytes and accrues their persistence in the LNs, by increasing the availability of the main egress signal S1P. Single-cell RNA-sequencing of tumor-draining LNs from WT and ATG5LEC-KO mice unveils that loss of ATG5 remodels niche-specific LEC phenotypes, involved in molecular pathways regulating lymphocyte trafficking and LEC-T cell interactions. Functionally, loss of LEC-autophagy prevents recruitment of tumor-infiltrating T cells and NK cells and abrogates tumor regression in response to anti-PD-1 or anti-CTLA4-based immunotherapy. Thus, a unique LEC-autophagy program boosts immune-checkpoint responses by guiding systemic T cell dynamics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/549282v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1a4bfe1org.highwire.dtl.DTLVardef@1317fe2org.highwire.dtl.DTLVardef@c2fa20org.highwire.dtl.DTLVardef@b35dba_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Trans-synaptic dwelling of SARS-CoV-2 particles perturbs neural synapse organization and function

SARS-CoV-2 infection is associated with short- and long-term neurological and psychiatric complications, referred to as neuroCOVID. These symptoms are relatively heterogenous and fluctuating, hampering the discovery of molecular mechanisms underlying viro-induced brain perturbations. Here, we show that the human cerebral cortex poorly supports SARS-CoV-2 dissemination using post-mortem COVID-19 patient samples, ex vivo organotypic cultures of human brain explants and stem cell-derived cortical organoids. Despite restricted infection, the sole exposure of neural cells to SARS-CoV-2 particles is sufficient to induce significant perturbations on neural synapse organization associated to electrical activity dysfunction. Single-organoid proteomics revealed that exposure to SARS-CoV-2 is associated to trans-synaptic proteins upregulation and unveiled that incoming virions dwell at LPHN3/FLRT3-containing synapses. Our study provides new mechanistic insights on the origin of SARS-CoV-2-induced neurological disorders. One-Sentence SummarySARS-CoV-2 modulates neural plasticity and electrical activity as viral particles lodge at the trans-synaptic interface.

microbiology↗

bioRxiv2022

Single-cell profiling identifies a spectrum of human unconventional intraepithelial T lineage cells

In the human thymus, a CD10+ PD-1+ TCR{beta}+ differentiation pathway diverges from the conventional single positive T cell lineages at the early double positive stage. These cells are phenotypically and functionally similar to murine unconventional intraepithelial lymphocyte (uIEL) precursors. Here, the progeny of the human uIEL lineage was identified in antigen-inexperienced blood. The uIELs in thymus and peripheral blood share a transcriptomic profile, characterized by hallmark transcription factors (i.e. ZNF683 and IKZF2), and polyclonal TCR repertoire with autoreactive features, exhibiting a bias towards early TCR alpha chain rearrangements. Single-cell RNA sequencing confirmed a common developmental trajectory between the thymic and peripheral uIELs, and clearly delineated this unconventional lineage in peripheral blood. This population is phenotypically defined as CD3+ TCR{beta}+ CD4- CCR7- CD26-. It contains CD10+ recent thymic emigrants, Helios+ KIR+ CD8+ Tregs and CD8+ T cells. Thus, the uIEL lineage represents a well-defined but heterogeneous, unconventional TCR{beta}+ lineage mostly confined in human within the CD8 single positive T cells. SummaryBilliet et al. identify the postthymic progeny of the intraepithelial lymphocyte precursors in human based on shared characteristics of the T cell receptor repertoire and the transcriptome. This lineage represents a well-defined but heterogeneous, unconventional TCR{beta}+ lineage mostly confined within the CD8 single positive T cells.

immunology↗

bioRxiv2022

An interactive mass spectrometry atlas of histone posttranslational modifications in T-cell acute leukemia

The holistic nature of omics studies makes them ideally suited to generate hypotheses on health and disease. Sequencing-based genomics and mass spectrometry (MS)-based proteomics are linked through epigenetic regulation mechanisms. However, epigenomics is currently mainly focused on DNA methylation status using sequencing technologies, while studying histone posttranslational modifications (hPTMs) using MS is lagging, partly because reuse of raw data is impractical. Yet, targeting hPTMs using epidrugs is an established promising research avenue in cancer treatment. Therefore, we here present the most comprehensive MS-based preprocessed hPTM atlas to date, including 21 T-cell acute lymphoblastic leukemia (T-ALL) cell lines. We present the data in an intuitive and browsable single licensed Progenesis QIP project and provide all essential quality metrics, allowing users to assess the quality of the data, edit individual peptides, try novel annotation algorithms and export both peptide and protein data for downstream analyses, exemplified by the PeptidoformViz tool. This data resource sets the stage for generalizing MS-based histone analysis and provides the first reusable histone dataset for epidrug development.

cancer biology↗

bioRxiv2021

DALI (Diversity AnaLysis Interface): a novel tool for the integrated analysis of multimodal single cell RNAseq data and immune receptor profiling.

Single-cell RNA sequencing is instrumental to unravel the cellular and transcriptomic heterogeneity of T and B cells in health and disease. Recent technological advances add additional layers of information allowing researchers to simultaneously explore the transcriptomic, surface protein and immune receptor diversity during adaptive immune responses. The increasing data complexity poses a burden on the workload for bioinformaticians, who are often not familiar with the specificities and biology of immune receptor profiling. The wet-lab modalities and sequencing capabilities currently have outpaced bioinformatics solutions, which forms an ever-increasing barrier for many biologists to analyze their datasets. Here, we present DALI (Diversity AnaLysis Interface), a software package to identify and analyze T cell and B cell receptor diversity in high-throughput single-cell sequencing data. DALI aims to support bioinformaticians with a functional toolbox, allowing seamless integration of multimodal scRNAseq and immune receptor profiling data generated through 10X Genomics Cell Ranger software. The R-based package builds further on workflows using the Seurat package and other existing tools for BCR/TCR analyses. In addition, DALI is designed to engage immunologists having limited coding experience with their data, using a browser-based interactive graphical user interface. The implementation of DALI can effectively lead to a two-way communication between wet-lab scientists and bioinformaticians to advance the analysis of complex datasets.

bioinformatics↗

bioRxiv2020

SOX11 is a lineage-dependency factor and master epigenetic regulator in neuroblastoma

The pediatric extra-cranial tumor neuroblastoma (NB) is characterised by a low mutation burden while copy number alterations are present in most high-risk cases. We identified SOX11 as a strong lineage dependency transcription factor in adrenergic NB based on recurrent chromosome 2p focal gains and amplifications, its specific expression in the normal sympatho-adrenal lineage and adrenergic NBs and its regulation by multiple adrenergic specific cis-interacting (super-)enhancers. Adrenergic NBs are strongly dependent on high SOX11 expression levels for growth and proliferation. Through genome-wide DNA-binding and transcriptome analysis, we identified and validated functional SOX11 target genes, several of which implicated in chromatin remodeling and epigenetic modification. SOX11 controls chromatin accessibility predominantly affecting distal adrenergic lineage-specific enhancers marked by binding sites of the adrenergic core regulatory circuitry. During normal sympathoblast differentiation we find expression of SOX11 prior to members of the adrenergic core regulatory circuitry. Given the broad control of SOX11 of multiple epigenetic regulatory complexes and its presumed pioneer factor function, we propose that adrenergic NB cells have co-opted the normal role of SOX11 as a crucial regulator of chromatin accessibility and cell identity.

cancer biology↗

bioRxiv2020

Single cell profiling of immature human postnatal thymocytes resolves the complexity of intra-thymic lineage differentiation and thymus seeding precursors.

During postnatal life, thymopoiesis depends on the continuous colonization of the thymus by bone marrow derived hematopoietic progenitors that migrate through the bloodstream. In human, the nature of these thymus immigrants has remained unclear. Here, we employ single-cell RNA sequencing on approximately 70.000 CD34+ thymocytes to unravel the heterogeneity of the human immature postnatal thymocytes. Integration of bone marrow and peripheral blood precursors datasets identifies several putative thymus seeding precursors that display heterogeneity for currently used surface markers as revealed by CITEseq. Besides T cell precursors, we discover branches of intrathymic developing dendritic cells with predominantly plasmacytoid DCs. Trough trajectory inference, we delineate the transcriptional dynamics underlying early human T-lineage development from which we predict transcription factor modules that drive stage-specific steps of human T cell development. Thus, our work resolves the heterogeneity of thymus seeding precursors in human and reveals the molecular mechanisms that drive their in vivo cell fate.

immunology↗

bioRxiv2019

A ‘Human-in-the-Loop’ Approach for Semi-automated Image Restoration in Electron Microscopy

The recent advent of 3D in Electron Microscopy (EM) has allowed for detection of detailed sub-cellular nanometer resolution structures. While being a scientific breakthrough, this has also caused an explosion in dataset size, necessitating the development of automated workflows. Automated workflows typically benefit reproducibility and throughput compared to manual analysis. The risk of automation is that it ignores the expertise of the microscopy user that comes with manual analysis. To mitigate this risk, this paper presents a hybrid paradigm. We propose a human-in-the-loop (HITL) approach that combines expert microscopy knowledge with the power of large-scale parallel computing to improve EM image quality through advanced image restoration algorithms. An interactive graphical user interface, publicly available as an ImageJ plugin, was developed to allow biologists to use our framework in an intuitive and user-friendly fashion. We show that this plugin improves visualization of EM ultrastructure and subsequent (semi-)automated segmentation and image analysis.

bioinformatics↗