A5007618638- Glioma Diagnosis and Treatment
- Cancer-related molecular mechanisms research
- Single-cell and spatial transcriptomics
- RNA Research and Splicing
- Congenital heart defects research
- Cancer Genomics and Diagnostics
- RNA modifications and cancer
- Cell Image Analysis Techniques
- MicroRNA in disease regulation
- Genomics and Chromatin Dynamics
- Marine animal studies overview
- Fetal and Pediatric Neurological Disorders
- Bat Biology and Ecology Studies
- Reproductive System and Pregnancy
- Cancer Cells and Metastasis
- Microtubule and mitosis dynamics
- Animal Vocal Communication and Behavior
- Birth, Development, and Health
- CAR-T cell therapy research
- Cancer-related Molecular Pathways
- Animal Behavior and Reproduction
- Advanced biosensing and bioanalysis techniques
- Immune cells in cancer
- Animal Genetics and Reproduction
- Mitochondrial Function and Pathology
DKFZ-ZMBH Alliance
2019-2025
Heidelberg University
2019-2025
Wellcome Sanger Institute
2024-2025
Wellcome/MRC Cambridge Stem Cell Institute
2024
University of Cambridge
2024
Heidelberg University
2024
European Molecular Biology Laboratory
2020
The expansion of the neocortex, a hallmark mammalian evolution
Sexually dimorphic traits are common among mammals and specified during development through the deployment of sex-specific genetic programs. Because little is known about these programs, we investigated them using a resource gene expression profiles in males females throughout five organs (human, mouse, rat, rabbit, opossum) bird (chicken). We found that sex-biased varied considerably across species was often cell-type specific. Sex differences increased abruptly around sexual maturity...
Combinations of transcription factors govern the identity cell types, which is reflected by genomic enhancer codes. We used deep learning to characterize these codes and devised three metrics compare types in telencephalon across amniotes. To this end, we generated single-cell multiome spatially resolved transcriptomics data chicken telencephalon. Enhancer orthologous nonneuronal γ-aminobutyric acid–mediated (GABAergic) show a high degree similarity amniotes, whereas excitatory neurons...
Innovations in the pallium likely facilitated evolution of advanced cognitive abilities birds. We therefore scrutinized its cellular composition and using cell type atlases from chicken, mouse, nonavian reptiles. found that avian shares most inhibitory neuron types with other amniotes. Whereas excitatory amniote hippocampal regions show evolutionary conservation, those pallial have diverged. Neurons mesopallium display gene expression profiles akin to mammalian claustrum deep cortical...
The cerebellum reveals its genetic programs Gene-regulatory networks govern the development of organs. Sarropoulos et al . analyzed mouse cerebellar in context gene-regulatory networks. Single nuclear profiles analyzing chromatin accessibility about 90,000 cells revealed diversity progenitor and guiding cellular differentiation. footsteps evolution were apparent varying constraints on different cell types. —PJH
Abstract Summary Visium HD by 10X Genomics is the first commercially available platform capable of capturing full scale transcriptomic data paired with a reference morphology image from archived FFPE blocks at sub-cellular resolution. However, aggregation capture regions to single cells poses challenges. Bin2cell reconstructs highest resolution (2 μm bins) leveraging segmentation and gene expression information. It compatible established Python cell spatial transcriptomics software, operates...
Identifying the molecular programs underlying human organ development and how they differ from model species is key for understanding health disease. Developmental gene expression profiles provide a window into genes direct means to compare them across species. We use transcriptomic resource covering of seven organs characterize temporal associated with distinct disease classes determine, each gene, similarity its spatiotemporal orthologs in rhesus macaque, mouse, rat, rabbit. find clear...
Abstract Background Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map cell-of-origin typically involved comparing human murine embryonal tissues, which potentially limited due species-specific differences. The aim this study was unravel 3 most common pediatric tumors, ependymoma, pilocytic astrocytoma, medulloblastoma, using a developing...
Combinations of transcription factors govern the identity cell types, which is reflected by enhancer codes in cis-regulatory genomic regions. Cell type-specific at nucleotide-level resolution have not yet been characterized for mammalian neocortex. It currently unknown whether these are conserved other vertebrate brains, and they informative to resolve homology relationships species that lack a neocortex such as birds. To compare types from with those bird pallium, we generated single-cell...
TP53 deficiency is the most common alteration in cancer; however, this alone typically insufficient to drive tumorigenesis. To identify genes promoting tumorigenesis combination with deficiency, we perform genome-wide CRISPR-Cas9 knockout screens coupled proliferation and transformation assays isogenic cell lines. Loss of several known tumor suppressors enhances cellular transformation. neddylation pathway promotes uncontrolled exclusively TP53-deficient cells. Combined loss CUL3 activates...
Abstract The advanced cognitive abilities of birds rival those mammals and have been attributed to evolutionary innovations in the pallium. However, a comprehensive cellular characterization this brain region has lacking. We scrutinized structures, cell types origins avian pallium based on single-cell spatial transcriptomics atlases for adult developing chicken, comparisons corresponding data from non-avian reptiles. found that shares most inhibitory neuron with other amniotes. While...
Gene regulatory changes are considered major drivers of evolutionary innovations, including the cerebellum's expansion during human evolution, yet they remain largely unexplored. In this study, we combined single-nucleus measurements gene expression and chromatin accessibility from six mammals (human, bonobo, macaque, marmoset, mouse, opossum) to uncover conserved diverged networks in cerebellum development. We identified core regulators cell identity developed sequence-based models that...
Abstract Despite recent advances in understanding disease biology, treatment of group 3/4 medulloblastoma remains a therapeutic challenge paediatric neuro-oncology 1 . Bulk-omics approaches have identified considerable intertumoural heterogeneity medulloblastoma, including the presence clear single-gene oncogenic drivers only subset cases, whereas most large-scale copy number aberrations prevail 2,3 However, intratumoural heterogeneity, role oncogene aberrations, and broad variation tumour...
Abstract Summary Visium HD by 10X Genomics is the first commercially available platform capable of capturing full scale transcriptomic data paired with a reference morphology image from archived FFPE blocks at sub-cellular resolution. However, aggregation capture regions to single cells poses challenges. Bin2cell reconstructs highest resolution (2 μ m bins) leveraging segmentation and gene expression information. It compatible established Python cell spatial transcriptomics software,...
The expansion of the neocortex, one hallmarks mammalian evolution 1,2 , was accompanied by an increase in number cerebellar neurons 3 . However, little is known about cellular programs underlying cerebellum development mammals. In this study, we generated single-nucleus RNA-sequencing data for ∼400,000 cells to trace from early neurogenesis adulthood human, mouse, and marsupial opossum. Our cross-species analyses revealed that composition differentiation dynamics throughout are largely...
Abstract Despite recent advances in understanding disease biology, treatment of Group 3/4 medulloblastoma remains a therapeutic challenge pediatric neuro-oncology. Bulk-omics approaches have identified considerable intertumoral heterogeneity medulloblastoma, including the presence clear single-gene oncogenic drivers only subset cases, whereas majority large-scale copy-number aberrations prevail. However, intratumoral heterogeneity, role oncogene aberrations, and broad CNVs tumor evolution...
Abstract Resolving the molecular mechanisms driving childhood brain tumors will uncover tumor-specific vulnerabilities and advance mechanism-of-action-based therapies. Here we describe a continuum of cell-states in Group 3/4 medulloblastomas, most frequent fatal cerebellar embryonal tumor subgroups, based on differential activity transcription-factor-driven gene networks derived using comprehensive single-nucleus multi-omic medulloblastoma atlas. We show that diversity stems from enriched...
Understanding the cellular origins of childhood brain tumors is key for discovering novel tumor-specific therapeutic targets. Previous strategies mapping typically involved comparing human to murine embryonal tissues 1,2 , a potentially imperfect approach due spatio-temporal gene expression differences between species 3 . Here we use an unprecedented single-nucleus atlas developing cerebellum (Sepp, Leiss, et al) and extensive bulk single-cell transcriptome tumor data map their with focus on...
Abstract Intra-tumor heterogeneity in brain cancers contributes to therapy resistance and relapse through positive selection of resistant tumor cell populations. Resolving the molecular mechanisms driving intra-tumor will uncover tumor-specific vulnerabilities advance effective treatment strategies. Group 3/4 medulloblastomas, most common embryonal cerebellar subgroup, are highly heterogeneous tumors with high frequency which almost certainly fatal. Here, we generated analyzed a...
Abstract Organ development is orchestrated by cell- and time-specific gene regulatory networks. Here we investigated the basis of mouse cerebellum from early neurogenesis to adulthood. By acquiring snATAC-seq profiles for ~90,000 cells spanning eleven stages, mapped all major cerebellar cell types identified candidate cis -regulatory elements (CREs). We detected extensive spatiotemporal heterogeneity among progenitor characterized programs underlying differentiation neurons. Although CRE...
Abstract The hindbrain is a key central nervous system structure involved in communication between the brain and spinal cord, integrating sensory information coordinating motor responses. Dysregulation development frequently associated with behavioral disorders maybe tumor formation, stressing importance of understanding intricacies human development. Here we performed RNA-sequencing over 300,000 single nuclei to construct developing atlas, focusing on pons medulla, ranging from embryonic...
Abstract Understanding the cellular origins of cerebellar tumors at single cell resolution may help identify novel therapeutic vulnerabilities to overcome current impediments in pediatric neuro-oncology. One approach answer this important question involves mapping tumor profiles onto normal embryonal central nervous system development. Previous attempts regard focused on integrating human data with developing mouse cerebellum atlases, however, these approaches were inherently limited due...