Biology subjects

Preissl, S.

Publications and source records attributed to Preissl, S..

At least 19 recordsLinked to original sources

bioRxiv2025

Multi-omic analysis of photoreceptor alterations during early-onset retinal degeneration in Mfrp-/- mice

Loss-of-function mutations in the membrane frizzled-related protein (MFRP) gene are associated with autosomal recessive ocular disorders such as nanophthalmos, posterior microphthalmia, and retinitis pigmentosa, yet the molecular mechanisms underlying MFRP-related retinal degeneration remain poorly defined. To investigate these mechanisms, we generated and characterized Mfrp-/- mice and conducted an integrated multi-omic analysis to map the onset and progression of transcriptional changes during retinal degeneration. Using longitudinal in vivo imaging, histological and immunohistochemical analysis, qRT-PCR, single-nucleus RNA sequencing (snRNA-seq), snATAC seq (single-nucleus Assay for Transposase-Accessible Chromatin using sequencing) and spatial transcriptomics (GeoMx DSP), we identified early and progressive photoreceptor loss in Mfrp-/- mice, beginning by 28d. Retinal thinning and autofluorescent deposits in Mfrp-/- mice were accompanied by decreased expression of rod and cone opsins. Transcriptomic profiling by snRNA-seq revealed distinct, photoreceptor-specific gene expression changes, including early upregulation of inflammatory and stress-related genes and later downregulation of genes involved in chromatin remodeling, synaptic function, and neurodevelopment. Spatial transcriptomic analysis of the outer nuclear layer (ONL) revealed disruptions in mitochondrial function, mTORC1 signaling, and G protein-coupled receptor pathways. These findings define a temporally and spatially coordinated program of degeneration triggered by Mfrp loss and demonstrate that Mfrp is required for the maintenance of photoreceptor integrity and gene regulatory homeostasis during retinal development. Our work establishes Mfrp-/- mice as a robust model for dissecting photoreceptor vulnerability and provides a transcriptomic atlas of disease progression with potential relevance for therapeutic development in MFRP-associated retinal dystrophies.

genomics↗

bioRxiv2025

Single-Cell Epigenomics Uncovers Heterochromatin Instability and Transcription Factor Dysfunction during Mouse Brain Aging

The mechanisms regulating transcriptional changes in brain aging remain poorly understood. Here, we use single-cell epigenomics to profile chromatin accessibility and gene expression across eight brain regions in the mouse brain at 2, 9, and 18 months of age. In addition to a significant decline in progenitor cell populations involved in neurogenesis and myelination, we observed widespread and concordant changes of transcription and chromatin accessibility during aging in glial and neuronal cell types. These alterations are accompanied by dysregulation of master transcription factors and a shift toward stress-responsive programs driven by AP-1, indicating a progressive loss of cell identity with aging. We also identify region- and cell-type-specific heterochromatin decay, characterized by increased accessibility at H3K9me3-marked domains, activation of transposable elements, and upregulation of long non-coding RNAs, particularly in glutamatergic neurons. Together, these results reveal age-related disruption of heterochromatin maintenance and transcriptional programs, identify vulnerable brain regions and cell types, and pinpoint key molecular pathways altered in brain aging. HighlightsO_LISingle-cell multimodal profiling across eight brain regions reveals coordinated chromatin and transcriptional shifts during aging C_LIO_LIAge-related depletion of progenitor cells coincides with dysregulation of key developmental transcription factors C_LIO_LICell identity maintenance is compromised with the decline of master transcription factors C_LIO_LIHeterochromatin destabilization accompanied by activation of AP-1, transposable elements, pseudogene families, and long non-coding RNAs C_LI

genomics↗

bioRxiv2025

Human Body Single-Cell Atlas of 3D Genome Organization and DNA Methylation

Higher-order chromatin structure and DNA methylation are critical for gene regulation, but how these vary across the human body remains unclear. We performed multi-omic profiling of 3D genome structure and DNA methylation for 86,689 single nuclei across 16 human tissues, identifying 35 major and 206 cell subtypes. We revealed extensive changes in CG and non-CG methylation across almost all cell types and characterized 3D chromatin structure at an unprecedented cellular resolution. Intriguingly, extensive discrepancies exist between cell types delineated by DNA methylation and genome structure, indicating that the role of distinct epigenomic features in maintaining cell identity may vary by lineage. This study expands our understanding of the diversity of DNA methylation and chromatin structure and offers an extensive reference for exploring gene regulation in human health and disease.

genomics↗

bioRxiv2025

Single-cell multiome and spatial profiling reveals pancreas cell type-specific gene regulatory programs driving type 1 diabetes progression

Cell type-specific regulatory programs that drive type 1 diabetes (T1D) in the pancreas are poorly understood. Here we performed single nucleus multiomics and spatial transcriptomics in up to 32 non-diabetic (ND), autoantibody-positive (AAB+), and T1D pancreas donors. Genomic profiles from 853,005 cells mapped to 12 pancreatic cell types, including multiple exocrine sub- types. Beta, acinar, and other cell types, and related cellular niches, had altered abundance and gene activity in T1D progression, including distinct pathways altered in AAB+ compared to T1D. We identified epigenomic drivers of gene activity in T1D and AAB+ which, combined with genetic association, revealed causal pathways of T1D risk including antigen presentation in beta cells. Finally, single cell and spatial profiles together revealed widespread changes in cell-cell signaling in T1D including signals affecting beta cell regulation. Overall, these results revealed drivers of T1D progression in the pancreas, which form the basis for therapeutic targets for disease prevention.

genomics↗

bioRxiv2025

Mycobacterial infection uncovers plasticity of Kupffer cells

Bona fide Kupffer cells (KCs) are prenatally seeded and show unique functional and immunophenotypic features among tissue macrophages. They are considered as terminally differentiated, and adaptability in disease is attributed to recruited, monocyte-derived KCs. Here, we investigated the extent of KC plasticity and the impact of origin in mycobacterial infections that target macrophages and can persist for months. Fate-mapping combined with high-resolution imaging revealed the emergence of a unique, infection specific KC subset which downregulated the signature markers CLEC4F and VSIG4 ("KClow"). KClow were derived from bona fide KCs and located exclusively to granuloma cores. In contrast, monocyte-derived macrophages were contained at the granuloma borders and contributed to this tissue reaction. ATAC and single-cell RNA sequencing identified a specific signature of KClow with high antimycobacterial activity and specialization to a hypoxic microenvironment. Despite their fundamental deviation from the classical KC phenotype, KClow showed remarkable adaptability, and were capable to return to a homeostatic-like KC state. Accordingly, mycobacterial infections unmask KCs as highly plastic cells, capable of responding to extreme environmental changes.

immunology↗

bioRxiv2024

Single-cell analysis of the epigenome and 3D chromatin architecture in the human retina

Most genetic risk variants linked to ocular diseases are non-protein coding and presumably contribute to disease through dysregulation of gene expression, however, deeper understanding of their mechanisms of action has been impeded by an incomplete annotation of the transcriptional regulatory elements across different retinal cell types. To address this knowledge gap, we carried out single-cell multiomics assays to investigate gene expression, chromatin accessibility, DNA methylome and 3D chromatin architecture in human retina, macula, and retinal pigment epithelium (RPE)/choroid. We identified 420,824 unique candidate regulatory elements and characterized their chromatin states in 23 sub-classes of retinal cells. Comparative analysis of chromatin landscapes between human and mouse retina cells further revealed both evolutionarily conserved and divergent retinal gene-regulatory programs. Leveraging the rapid advancements in deep-learning techniques, we developed sequence-based predictors to interpret non-coding risk variants of retina diseases. Our study establishes retina-wide, single-cell transcriptome, epigenome, and 3D genome atlases, and provides a resource for studying the gene regulatory programs of the human retina and relevant diseases.

genomics↗

bioRxiv2024

Single cell multiome profiling of pancreatic islets reveals physiological changes in cell type-specific regulation associated with diabetes risk

Physiological variability in pancreatic cell type gene regulation and the impact on diabetes risk is poorly understood. In this study we mapped gene regulation in pancreatic cell types using single cell multiomic (joint RNA-seq and ATAC-seq) profiling in 28 non-diabetic donors in combination with single cell data from 35 non-diabetic donors in the Human Pancreas Analysis Program. We identified widespread associations with age, sex, BMI, and HbA1c, where gene regulatory responses were highly cell type- and phenotype-specific. In beta cells, donor age associated with hypoxia, apoptosis, unfolded protein response, and external signal-dependent transcriptional regulators, while HbA1c associated with inflammatory responses and gender with chromatin organization. We identified 10.8K loci where genetic variants were QTLs for cis regulatory element (cRE) accessibility, including 20% with lineage- or cell type-specific effects which disrupted distinct transcription factor motifs. Type 2 diabetes and glycemic trait associated variants were enriched in both phenotype- and QTL-associated beta cell cREs, whereas type 1 diabetes showed limited enrichment. Variants at 226 diabetes and glycemic trait loci were QTLs in beta and other cell types, including 40 that were statistically colocalized, and annotating target genes of colocalized QTLs revealed genes with putatively novel roles in disease. Our findings reveal diverse responses of pancreatic cell types to phenotype and genotype in physiology, and identify pathways, networks, and genes through which physiology impacts diabetes risk.

genomics↗

bioRxiv2024

The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma

Whether an individual is a biological female or male affects cancer risk, but the responsible mechanisms and cell types remain obscure. Glioblastoma multiforme (GBM) is a male-biased cancer that is highly aggressive, and resistant to treatment, with poor patient survival. Dismal prognoses in GBM are due in part to the specialized immune system of the brain, consisting largely of microglia, which regulate GBM development and progression. We hypothesized that microglia function differently in females and males and thereby contribute to the observed male bias in GBM. We sorted TAM-MGs (tumor-associated macrophages - microglia) from human GBMs and low-grade gliomas and performed bulk transcriptomic and epigenomic assays to identify sex-biased gene expression. We used published single-cell transcriptomic data from human GBMs to predict sex-biased TAM-MG interactions with other cell types. We found that female and male TAM-MGs mount different inflammatory responses, with female TAM-MGs displaying stronger interferon signaling and cytotoxic T-cell interactions that should enhance anti-tumor immunity in GBM. We validated these sex-differential inflammatory responses experimentally, and determined that genes on the sex chromosomes, specifically those expressed by Xi (the "inactive" X chromosome), drive these differences. Together, our results suggest that sex-differential TAM-MG inflammatory responses contribute to the higher incidence and mortality of GBM in males.

genomics↗

bioRxiv2023

Age-related structural and functional changes of the intracardiac nervous system

BackgroundAlthough aging is known to be associated with an increased incidence of both atrial and ventricular arrhythmias, there is limited knowledge about how Schwann cells (SC) and the intracardiac nervous system (iCNS) remodel with age. Here we investigate the differences in cardiac SC, parasympathetic nerve fibers, and muscarinic acetylcholine receptor M2 (M2R) expression in young and old mice. Additionally, we examine age-related changes in cardiac responses to sympathomimetic and parasympathomimetic drugs. Methods and ResultsLower SC density, lower SC proliferation and fewer parasympathetic nerve fibers were observed in cardiac and, as a control sciatic nerves from old (20-24 months) compared to young mice (2-3 months). In old mice, CSPG4 was increased in sciatic but not cardiac nerves. Expression of M2R was lower in ventricular myocardium and ventricular conduction system from old mice compared to young mice, while no significant difference was seen in M2R expression in sino-atrial or atrio-ventricular node pacemaker tissue. Heart rate was slower and PQ intervals were longer in Langendorff-perfused hearts from old mice. Ventricular tachycardia and fibrillation were more frequently observed in response to carbachol administration in hearts from old mice versus those from young mice. ConclusionsOn the background of reduced presence of SC and parasympathetic nerve fibers, and of lower M2R expression in ventricular cardiomyocytes and conduction system of aged hearts, the propensity of ventricular arrhythmogenesis upon parasympathomimetic drug application is increased. Whether this is caused by an increase in heterogeneity of iCNS structure and function remains to be elucidated. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/568538v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@11dbccdorg.highwire.dtl.DTLVardef@1563d75org.highwire.dtl.DTLVardef@dcda58org.highwire.dtl.DTLVardef@182e598_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2023

Cell Type- and Tissue-specific Enhancers in Craniofacial Development

The genetic basis of craniofacial birth defects and general variation in human facial shape remains poorly understood. Distant-acting transcriptional enhancers are a major category of non-coding genome function and have been shown to control the fine-tuned spatiotemporal expression of genes during critical stages of craniofacial development1-3. However, a lack of accurate maps of the genomic location and cell type-specific in vivo activities of all craniofacial enhancers prevents their systematic exploration in human genetics studies. Here, we combined histone modification and chromatin accessibility profiling from different stages of human craniofacial development with single-cell analyses of the developing mouse face to create a comprehensive catalogue of the regulatory landscape of facial development at tissue- and single cell-resolution. In total, we identified approximately 14,000 enhancers across seven developmental stages from weeks 4 through 8 of human embryonic face development. We used transgenic mouse reporter assays to determine the in vivo activity patterns of human face enhancers predicted from these data. Across 16 in vivo validated human enhancers, we observed a rich diversity of craniofacial subregions in which these enhancers are active in vivo. To annotate the cell type specificities of human-mouse conserved enhancers, we performed single-cell RNA-seq and single-nucleus ATAC-seq of mouse craniofacial tissues from embryonic days e11.5 to e15.5. By integrating these data across species, we find that the majority (56%) of human craniofacial enhancers are functionally conserved in mice, providing cell type- and embryonic stage-resolved predictions of their in vivo activity profiles. Using retrospective analysis of known craniofacial enhancers in combination with single cell-resolved transgenic reporter assays, we demonstrate the utility of these data for predicting the in vivo cell type specificity of enhancers. Taken together, our data provide an expansive resource for genetic and developmental studies of human craniofacial development. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=138 HEIGHT=200 SRC="FIGDIR/small/546603v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@7595a9org.highwire.dtl.DTLVardef@1b48b81org.highwire.dtl.DTLVardef@32fe86org.highwire.dtl.DTLVardef@1e41fed_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2023

An EOMES induced epigenetic deflection initiates lineage commitment at mammalian gastrulation

Summary paragraph Different cell types are determined by cell lineage-specific transcriptional programmes and by epigenetic regulation of chromatin1, 2. Yet, the functional relationships between dynamically expressed transcription factors (TFs) and chromatin changes guiding lineage specification often remain elusive3. First mammalian embryonic lineages segregate when pluripotent cells become committed to either Mesoderm and Endoderm (ME) or Neuroectoderm (NE). NE forms by default in the absence of signalling-induced ME specification4, 5, resulting from global asymmetries in chromatin state favouring NE gene programme activation as recently demonstrated6-8. In this study, we unravel the initiation of ME lineage specification by the genome-wide, de novo formation of chromatin accessibility at ME enhancers that epigenetically deflects pluripotent cells from default NE differentiation. The Tbx TF Eomes, previously considered a transcriptional regulator, acts as global chromatin organizer that establishes ME lineage competence. EOMES recruits the canonical ATP-dependent chromatin remodelling complex SWI/SNF to broadly generate the chromatin- accessible ME enhancer landscape. This lineage competence is generated independently of ME gene transcription that fully depends on ME-inducing signalling pathways including Wnts and TGF{beta}/NODAL9. This study thus resolves the successive steps of ME lineage differentiation by globally establishing chromatin accessibility for lineage competence, followed by signal-encoded transcriptional regulation of different ME lineage-defining gene programmes.

developmental biology↗

bioRxiv2022

A comparative atlas of single-cell chromatin accessibility in the human brain

The human brain contains an extraordinarily diverse set of neuronal and glial cell types. Recent advances in single cell transcriptomics have begun to delineate the cellular heterogeneity in different brain regions, but the transcriptional regulatory programs responsible for the identity and function of each brain cell type remain to be defined. Here, we carried out single nucleus ATAC-seq analysis to probe the open chromatin landscape from over 1.1 million cells in 42 brain regions of three neurotypical adult donors. Integrative analysis of the resulting data identified 107 distinct cell types and revealed the cell-type-specific usage of 544,735 candidate cis-regulatory DNA elements (cCREs) in the human genome. Nearly 1/3 of them displayed sequence conservation as well as chromatin accessibility in the mouse brain. On the other hand, nearly 40% cCREs were human specific, with chromatin accessibility associated with species-restricted gene expression. Interestingly, these human specific cCREs were enriched for distinct families of retrotransposable elements, which displayed cell-type-specific chromatin accessibility. We uncovered strong associations between specific brain cell types and neuropsychiatric disorders. We futher developed deep learning models to predict regulatory function of non-coding disease risk variants.

neuroscience↗

bioRxiv2022

Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes

Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, CDX2+ pre-{beta}-cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro {beta}-cell maturation and identify sex hormones as drivers of {beta}-cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem cell-derived islets and a framework for manipulating cell identities and maturity.

cell biology↗

bioRxiv2022

Cell-associated Transcriptional Alterations in the Retinal of Alzheimer's Disease

Current approaches for studying pathologic changes in the retina associated with Alzheimers Disease (AD) remain heterogeneous, limiting the use of retinal amyloid-beta as a viable biomarker for AD. Transcriptomic profiling of the retina has provided cell-specific insight into AD progression in the brain yet is lacking in the retina. In this study, we implemented a non-biased approach through next generation sequencing to profile frozen archived retinal tissues from autopsy/pathologically confirmed AD and non-diagnosed cases (NonAD). A total of 37,211 nuclei were isolated from frozen retinal tissue punches originating from AD, and 31,326 were isolated from non-diagnosed cases. Gene expression patterns specific to the retinal region and major retinal cell types were represented in both tissue groups. AD-associated genes were differentially expressed in AD retinal glial cells, including microglia. A greater percentage of microglial nuclei from AD retinal nuclei expressed TYRO protein tyrosine kinase-binding protein (TYROBP) compared to nonAD retinal nuclei. However, compared to microglia from single retinal cell datasets from elderly non-diseased individuals, TYROBP expression is highly expressed in the single cell data set, indicating TYROBP transcripts reside within the cytoplasm. However, other AD-associated genes were differentially expressed in AD nuclei such as DOCK2, PICALM, and PLCG2 compared to non-diseased single-cell microglia, implicating a role of these genes in the AD retina. To summarize, we extracted a high number of nuclei from frozen retinal tissue that retain specific gene markers for cell classification and highlighted candidate AD-associated genes in retinal microglia that may be viable in future AD retinal studies.

neuroscience↗

bioRxiv2021

Robust enhancer-gene regulation identified by single-cell transcriptomes and epigenomes

Integrating single-cell transcriptomes and epigenomes across diverse cell types can link genes with the cis-regulatory elements (CREs) that control expression. Gene co-expression across cell types confounds simple correlation-based analysis and results in high false prediction rates. We developed a procedure that controls for co-expression between genes and integrates multiple molecular modalities, and used it to identify >10,000 gene-CRE pairs that contribute to gene expression programs in different cell types in the mouse brain.

bioinformatics↗

bioRxiv2021

Gene regulatory networks underlying human microglia maturation

The fetal period is a critical time for brain development, characterized by neurogenesis, neural migration, and synaptogenesis1-3. Microglia, the tissue resident macrophages of the brain, are observed as early as the fourth week of gestation4 and are thought to engage in a variety of processes essential for brain development and homeostasis5-11. Conversely, microglia phenotypes are highly regulated by the brain environment12-14. Mechanisms by which human brain development influences the maturation of microglia and microglia potential contribution to neurodevelopmental disorders remain poorly understood. Here, we performed transcriptomic analysis of human fetal and postnatal microglia and corresponding cortical tissue to define age-specific brain environmental factors that may drive microglia phenotypes. Comparative analysis of open chromatin profiles using bulk and single-cell methods in conjunction with a new computational approach that integrates epigenomic and single-cell RNA-seq data allowed decoding of cellular heterogeneity with inference of subtype- and development stage-specific transcriptional regulators. Interrogation of in vivo and in vitro iPSC-derived microglia models provides evidence for roles of putative instructive signals and downstream gene regulatory networks which establish human-specific fetal and postnatal microglia gene expression programs and potentially contribute to neurodevelopmental disorders.

genomics↗

bioRxiv2021

A cell atlas of chromatin accessibility across 25 adult human tissues

Current catalogs of regulatory sequences in the human genome are still incomplete and lack cell type resolution. To profile the activity of human gene regulatory elements in diverse cell types and tissues in the human body, we applied single cell chromatin accessibility assays to 25 distinct human tissue types from multiple donors. The resulting chromatin maps comprising [~]500,000 nuclei revealed the status of open chromatin for over 750,000 candidate cis-regulatory elements (cCREs) in 54 distinct cell types. We further delineated cell type-specific and tissue-context dependent gene regulatory programs, and developmental stage specificity by comparing with a recent human fetal chromatin accessibility atlas. We finally used these chromatin maps to interpret the noncoding variants associated with complex human traits and diseases. This rich resource provides a foundation for the analysis of gene regulatory programs in human cell types across tissues and organ systems.

genomics↗

bioRxiv2021

Large-scale genetic association and single cell accessible chromatin mapping defines cell type-specific mechanisms of type 1 diabetes risk

Translating genome-wide association studies (GWAS) of complex disease into mechanistic insight requires a comprehensive understanding of risk variant effects on disease-relevant cell types. To uncover cell type-specific mechanisms of type 1 diabetes (T1D) risk, we combined genetic association mapping and single cell epigenomics. We performed the largest to-date GWAS of T1D in 489,679 samples imputed into 59.2M variants, which identified 74 novel association signals including several large-effect rare variants. Fine-mapping of 141 total signals substantially improved resolution of causal variant credible sets, which primarily mapped to non-coding sequence. To annotate cell type-specific regulatory mechanisms of T1D risk variants, we mapped 448,142 candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cell types using snATAC-seq of 131,554 nuclei. T1D risk variants were enriched in cCREs active in CD4+ T cells as well as several additional cell types including pancreatic exocrine acinar and ductal cells. High-probability T1D risk variants at multiple signals mapped to exocrine-specific cCREs including novel loci near CEL, GP2 and CFTR. At the CFTR locus, the likely causal variant rs7795896 mapped in a ductal-specific distal cCRE which regulated CFTR and the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in T1D pathogenesis and highlight the power of combining large-scale GWAS and single cell epigenomics to provide insight into the cellular origins of complex disease.

genetics↗