Biology subjects

Sauer, S.

Publications and source records attributed to Sauer, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Multilevel sex-specific neurobiological signatures of early life adversity

Stress exposure early in life is an established risk factor for adult psychiatric illness, yet these disorders - including anxiety disorders and depression - show significant sex-dependence in prevalence, symptomatology, and treatment response. The biology underlying these differences remains largely unexplored and may contribute to the clinical heterogeneity in anxiety and depression. Here, we characterize the lasting impact of developmental stress on adulthood neurobiology and behavior in mice by combining analyses of multiple levels of brain function, including whole-brain c-Fos mapping, manganese-enhanced MRI and transcriptomics with advanced behavioral phenotyping. Across levels of investigation, we find distinct and often opposite effects of developmental stress depending on sex. These results together showcase the strong influence of sex on how early life adversity affects the onset of stress-related disorders. This work emphasizes the necessity of considering sex when investigating developmental and neurobiological underpinnings of stress-related disorders and displays a vast range of lasting effects of developmental stress on the brain, which provides a valuable resource for future studies aiming to improve psychiatric treatments.

neuroscience↗

bioRxiv2025

Lower cortical FKBP5 DNA methylation at key enhancer sites is associated with older age and higher gene expression in schizophrenia

An increasingly compelling body of literature indicates the glucocorticoid receptor cochaperone FK506-binding protein 51 (FKBP51) is a promising target for novel psychiatric therapeutics. However, the mechanisms regulating the corresponding FKBP5 gene directly in the human brain remain largely unknown yet are needed to facilitate the development of precise mechanism-based treatment approaches. Here, we examined FKBP5 DNA methylation patterns in postmortem human brain samples from the dorsolateral prefrontal cortex of individuals who lived with a major psychiatric disorder (schizophrenia, major depression, or bipolar disorder; n=329) and controls n=231. We identified that cytosine-phosphate-guanine-dinucleotide (CpG) specific FKBP5 DNA methylation is altered in psychiatric disorders across the FKBP5 locus, and that these changes are differentially associated with age and genotype (rs1360780 CC vs CT/TT). Individuals with schizophrenia had significantly lower levels of DNA methylation in the proximal enhancer of FKBP5, which also negatively correlated with FKBP5 gene expression. These changes were also associated with predicted glucocorticoid response elements (GREs) in the proximal enhancer, but not other transcription factor binding sites. This evidence supports that in the human cortex, FKBP5 DNA methylation is associated with both genetic and ageing effects, and that the associations between these factors vary at a diagnosis-specific level in psychopathology. This may have implications for developing FKBP5-targeted therapeutics and defining a subgroup of patients who will benefit from such treatments.

neuroscience↗

bioRxiv2024

Oncogene inactivation-induced senescence facilitates tumor relapse

Oncogene-directed therapies can induce profound tumor regression in oncogene-addicted cancers such as BRAF-mutant melanoma and KRAS-driven pancreatic cancer, but their long-term benefit is often limited by resistance and early relapse. The mechanisms that allow residual cells to adapt, persist in a dormant state, and eventually fuel recurrence remain poorly understood. Here, we show that oncogene inactivation rapidly induces hallmark features of senescence together with a pro-inflammatory senescence-associated secretory phenotype (SASP). In vivo, oncogene inactivation-induced senescence (OIIS) predisposed tumors to relapse, characterized by polyploidy, chromosomal instability, and acquisition of alternative oncogenic pathways such as Mdm2 upregulation. Tumor microenvironment profiling by spectral flow cytometry revealed that relapse was associated with neovascularization and a shift from an immune-activated to an immunosuppressive milieu, indicating that senescent cells remodel their niche to promote regrowth. Importantly, OIIS features were also observed in human BRAFV600E melanoma cells treated with vemurafenib, confirming the clinical relevance of our findings. Together, our findings establish OIIS as a double-edged process: it initially restrains tumor growth but simultaneously creates conditions that favor recurrence. By defining the genetic, metabolic, cytogenetic, and microenvironmental hallmarks of OIIS, our study highlights adaptations to oncogene deprivation that limit the durability of targeted therapies.

cancer biology↗

bioRxiv2024

From in vitro to in silico: a pipeline for generating virtual tissue simulations from real image data

3D cell culture models replicate tissue complexity, aiming to study cellular interactions and responses in a more physiologically relevant environment compared to traditional 2D cultures. However, the spherical structure of these models makes it difficult to extract meaningful data, necessitating advanced techniques for proper analysis. In silico simulations enhance research by predicting cellular behaviors and therapeutic responses, providing a powerful tool to complement experimental approaches. Despite their potential, these simulations often require advanced computational skills and significant resources, creating a barrier for many researchers. To address these challenges, we developed an accessible pipeline using open-source software to facilitate virtual tissue simulations. Our approach employs the Cellular Potts Model, a versatile framework for simulating cellular behaviors in tissues. The simulations are constructed from real world 3D image stacks of cancer spheroids, ensuring the virtual models are rooted in experimental data. By introducing a new metric for parameter optimization, we enable the creation of realistic simulations without requiring extensive computational expertise. This pipeline benefits researchers wanting to incorporate computational biology into their methods, even if they do not possess extensive expertise in this area. By reducing the technical barriers associated with advanced computational modeling, our pipeline allows more researchers to utilize these powerful tools. Our approach aims to foster broader use of in silico methods in disease research, contributing to a deeper understanding of disease biology and the refinement of therapeutic interventions.

biophysics↗

bioRxiv2024

Huntingtin CAG repeat size variations outside the Huntington's disease complex: associations with depression and anxiety phenotypes and basal ganglia structure

Huntingtons Disease (HD) is strongly associated with psychiatric symptoms, yet, associations between Huntingtin gene (HTT) CAG repeat size variations and psychiatric phenotypes outside the HD complex are still under-investigated. In this genetic case-control study we compared the distribution of HTT CAG repeat sizes in predefined ranges between patients with major depressive disorder (MDD) (n=2136) and anxiety disorders (ANX) (n=493), and healthy controls (CON) (n=1566). We used regression models to study interactions between the alleles and associations with fine-granular clinical phenotypes and basal ganglia structure. HD mutations in the range of incomplete penetrance (36-39 repeats) were not overrepresented in patients. In participants older than 48 years, 13-20 repeats on both HTT alleles were associated with a reduced ANX risk whereas a 13-20|21-26 combination was associated with an increased ANX risk. Post-hoc analyses confirmed a turning point around 21 repeats and trends in the same direction were detected for MDD. The joint patient|CON analysis of the full spectrum of allele combinations confirmed interaction effects and age-dependent allele|risk profiles. A short-by-long interaction effect and an age-dependent negative correlation of the short allele on the nucleus accumbens volume was detected, independently of the diagnostic group. In conclusion, we revealed that HTT CAG repeat sizes of both alleles in the non-HD range modulate the susceptibility for common psychiatric disorders and basal ganglia structure in an age-dependent way, displaying that normal variation of the functionally diverse wildtype huntingtin protein may already impact brain function.

genetics↗

bioRxiv2024

Extensive folding variability between homologous chromosomes in mammalian cells

Genetic variation and 3D chromatin structure have major roles in gene regulation. Due to challenges in mapping chromatin conformation with haplotype-specific resolution, the effects of genetic sequence variation on 3D genome structure and gene expression imbalance remain understudied. Here, we applied Genome Architecture Mapping (GAM) to a hybrid mouse embryonic stem cell (mESC) line with high density of single nucleotide polymorphisms (SNPs). GAM resolved haplotype-specific 3D genome structures with high sensitivity, revealing extensive allelic differences in chromatin compartments, topologically associating domains (TADs), long-range enhancer-promoter contacts, and CTCF loops. Architectural differences often coincide with allele-specific differences in gene expression, mediated by Polycomb repression. We show that histone genes are expressed with allelic imbalance in mESCs, are involved in haplotype-specific chromatin contact marked by H3K27me3, and are targets of Polycomb repression through conditional knockouts of Ezh2 or Ring1b. Our work reveals highly distinct 3D folding structures between homologous chromosomes, and highlights their intricate connections with allelic gene expression.

genomics↗

bioRxiv2024

A Multiparametric Analysis Reveals Differential Behavior of Spheroid Cultures on Distinct Ultra-Low Attachment Plates Types

Spheroids have become principal three-dimensional biological models to study cancer, developmental processes, and drug efficacy. For spheroid generation, ultra-low attachment plates are noteworthy due to their simplicity, compatibility with automation, and experimental and commercial accessibility. Nonetheless, it is unknown whether and to what degree the plate type impacts spheroid formation and biology. This study employed automated brightfield microscopy to systematically compare the size and eccentricity of spheroids formed in six different plate types using four distinct human cell lines, i.e., CCD-1137Sk fibroblasts, HaCaT keratinocytes, and MDA-MB-231 and HT-29 cancer cells. Results showed that all plate types exhibited similar sphe-roid-forming capabilities, and the gross patterns of growth or shrinkage during four days after seeding were comparable. Yet, size and eccentricity varied systematically among specific cell lines and plate types. A confocal wholemount analysis by a novel pipeline of AI-based 3D-image analysis procedures revealed changes in cell proliferation, cell number, nuclear volume, and keratino-cyte differentiation, which were accompanied by altered YAP1-signals. The findings show that the plate type may influence the outcome of experimental campaigns. It is advisable to scan different plate types for the optimal configuration for a specific investigation instead of using one standard plate for all kinds of applications.

cancer biology↗

bioRxiv2022

Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

The human adrenal gland is a complex endocrine tissue. Developmental studies on this tissue have been limited to animal models or human foetus. Here, we present a cell atlas analysis of the adult human normal adrenal gland, combining single-nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland development and tumourigenesis. We identified two populations of potential progenitor cells resident within the adrenal cortex: adrenocortical progenitors NR2F2+-ID1+ cells, located within and underneath the capsule, and medullary progenitors SYT1+-CHGA- cells, located in islets in the subcapsular region. Using pseudotime analyses, we provided evidence of the centripetal nature of adrenocortical cell development and of the essential role played by the Wnt/{beta}-catenin pathway in the adrenocortical self-renewal. By comparing transcriptional profiles of cells of normal adrenal glands and adrenocortical adenomas we revealed a high heterogeneity with six adenoma-specific clusters. Overall, our results give insights into adrenal plasticity and mechanisms underlying adrenocortical tumourigenesis.

physiology↗

bioRxiv2022

Temporal regulation of ZBTB16 expression by glucocorticoids alters human cortical neurogenesis

Glucocorticoids are important for proper organ maturation and their levels are tightly regulated during development. Here we use human cerebral organoids and mice to study cell-type specific effects of glucocorticoids on neurogenesis. We show that glucocorticoids increase a specific type of basal progenitors (co-expressing PAX6 and EOMES) that has been shown to drive cortical expansion in gyrified species. This effect is mediated via the transcription factor ZBTB16 and leads to increased production of neurons. A phenome-wide mendelian randomization analysis of an enhancer variant that moderates glucocorticoid-induced ZBTB16 levels, reveals causal relationships with higher educational attainment and altered brain structure. The relationship with postnatal cognition is supported by data from a prospective pregnancy cohort. This study provides a novel cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that relates to lasting postnatal phenotypes.

neuroscience↗

bioRxiv2022

DiffBrainNet: differential analyses add new insights into the response to glucocorticoids at the level of genes, networks and brain regions

Genome-wide gene expression analyses are invaluable tools for increasing our knowledge of biological and disease processes, allowing a hypothesis-free comparison of gene expression profiles across experimental groups, tissues and cell types. Traditionally, transcriptomic data analysis has focused on gene-level effects found by differential expression. In recent years, network analysis has emerged as an important additional level of investigation, providing information on molecular connectivity, especially for diseases associated with a large number of linked effects of smaller magnitude, like neuropsychiatric disorders and their risk factors, including stress. In this manuscript, we describe how combined differential expression and prior-knowledge-based differential network analysis can be used to explore complex datasets. As an example, we analyze the transcriptional responses following administration of the glucocorticoid/stress hormone receptor agonist dexamethasone in C57Bl/6 mice, in 8 brain regions important for stress processing: the prefrontal cortex, the amygdala, the paraventricular nucleus of the hypothalamus, the cerebellar cortex, and sub regions of the hippocampus: the dorsal and ventral Cornu Ammonis 1, the dorsal and ventral dentate gyrus. By applying a combination of differential network- and differential expression-analyses, we find that these explain distinct but complementary aspects and biological mechanisms of the responses to the stimulus. In addition, network analysis identifies new differentially connected partners of important genes and can be used to generate hypotheses on specific molecular pathways affected. With this work, we provide an analysis framework and a publicly available resource for the study of the transcriptional landscape of the mouse brain: DiffBrainNet (http://diffbrainnet.psych.mpg.de), which can identify molecular pathways important for basic functioning and response to glucocorticoids in a brain-region specific manner.

genomics↗

bioRxiv2022

Non-productive exposure of PBMCs to SARS-CoV-2 induces cell-intrinsic innate immunity responses

Cell-intrinsic responses mounted in vivo in PBMCs during mild and severe COVID-19 differ quantitatively and qualitatively. Whether they are triggered by signals emitted by productively infected cells of the respiratory tract or are, at least partially, resulting from physical interaction with virus particles, remains unclear. Here, we analyzed susceptibility and expression profiles of PBMCs from healthy donors upon ex vivo exposure to SARS-CoV and SARS-CoV-2. In line with the absence of detectable ACE2 receptor expression, human PBMCs were refractory to productive infection. Bulk and single cell RNA-sequencing revealed JAK/STAT-dependent induction of interferon-stimulated genes, but not pro-inflammatory cytokines. This SARS-CoV-2-specific response was most pronounced in monocytes. SARS-CoV-2-RNA-positive monocytes displayed a lower ISG signature as compared to bystander cells of the identical culture. This suggests a preferential invasion of cells with a low ISG base-line profile or delivery of a SARS-CoV-2-specific sensing antagonist upon efficient particle internalization. Together, non-productive physical interaction of PBMCs with SARS-CoV-2-but not SARS-CoV particles stimulates JAK/STAT-dependent, monocyte-accentuated innate immune responses that resemble those detected in vivo in patients with mild COVID-19.

immunology↗

bioRxiv2021

Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria (MMAuria), present unique challenges to energetic homeostasis by disrupting energy producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut) type MMAuria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared to littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these indicate hypometabolism, energetic inflexibility and increased stores at the expense of active tissue as energy shortage consequences.

physiology↗

bioRxiv2021

Diverse but unique astrocytic phenotypes during embryonic stem cell differentiation, culturing and aging

Astrocytes are resident glia cells of the central nervous system (CNS) that play complex and heterogeneous roles in brain development, homeostasis and disease. Since their vast involvement in health and disease is becoming increasingly recognized, suitable and reliable tools for studying these cells in vivo and in vitro are of utmost importance. One of the key challenges hereby is to adequately mimic their context-dependent in vivo phenotypes and functions in vitro. To better understand the spectrum of astrocytic variations in defined settings we performed a side-by-side-comparison of embryonic stem cell (ESC)-derived astrocytes as well as primary neonatal and adult astrocytes, revealing major differences on a functional and transcriptomic level, specifically on proliferation, migration, calcium signaling and cilium activity. Our results highlight the need to carefully consider the choice of astrocyte origin and phenotype with respect to age, isolation and culture protocols based on the respective biological question.

neuroscience↗

bioRxiv2020

Single-nuclei RNA-sequencing of plants

Single-cell genomics provides unprecedented potential for research on plant development and environmental responses. Here, we introduce a generic procedure for plant nuclei isolation combined with nanowell-based library preparation. Our method enables the transcriptome analysis of thousands of individual plant nuclei. It serves as alternative to the use of protoplast isolation, which is currently a standard methodology for plant single-cell genomics, although it can be challenging for some plant tissues. We show the applicability of our nuclei isolation method by using different plant materials from several species. The potential of our snRNA-seq method is shown through the characterization of transcriptomes of seedlings and developing flowers from Arabidopsis thaliana. We evaluated the transcriptome dynamics during the early stages of anther development, identify stage-specific transcription factors regulating this process and the prediction of their target genes. Our nuclei isolation procedure can be applied in different plant species and tissues, thus expanding the toolkit for plant single-cell genomics experiments. SIGNIFICANCE STATEMENTWe introduce an optimized plant nuclei isolation procedure followed by single nuclei RNA-seq that can be applied to different plant tissues without the need for protoplast isolation.

genomics↗

bioRxiv2020

Urbanization promotes specific bacteria in freshwater microbiomes including potential pathogens

Freshwater ecosystems are characterized by complex and highly dynamic microbial communities that are strongly structured by their local environment and biota. Growing city populations and the process of urbanization substantially alter freshwater environments. To determine the changes in freshwater microbial communities associated with urbanization, full-length 16S rRNA gene PacBio sequencing was performed from surface water and sediments from a wastewater treatment plant, urban and rural lakes in the Berlin-Brandenburg region, Northeast Germany. Water samples exhibited highly habitat specific bacterial communities with multiple genera showing clear urban signatures. We identified potentially harmful bacterial groups associated with environmental parameters specific to urban habitats such as Alistipes, Escherichia/Shigella, Rickettsia and Streptococcus. We demonstrate that urbanization alters natural microbial communities in lakes and, via simultaneous eutrophication, creates favorable conditions that promote specific bacterial genera including potential pathogens. Our findings are of global relevance highlighting a long-term health risk in urbanized waterbodies, at a time of accelerated global urbanization. The results demonstrate the urgency for undertaking mitigation measures such as targeted lake restoration projects and sustainable water management efforts.

microbiology↗

bioRxiv2020

Dissecting HSV-1-induced host shut-off at RNA level

Herpes simplex virus 1 (HSV-1) installs a profound host shut-off during lytic infection. The virion host shut-off (vhs) protein plays a key role in this process by efficiently cleaving both host and viral mRNAs in a translation-initiation-dependent manner. Furthermore, the onset of viral DNA replication is accompanied by a rapid decline in transcriptional activity of the host genome. Both mechanisms have tremendous impact on the RNA expression profile of the infected cells. To dissect their relative contributions and elucidate gene-specific host transcriptional responses throughout the first 8h of lytic HSV-1 infection, we here employed RNA-seq of total, newly transcribed (4sU-labelled) and chromatin-associated RNA in wild-type (WT) and {Delta}vhs infection of primary human fibroblasts. Following virus entry, vhs activity rapidly plateaued at an elimination rate of around 30% of cellular mRNAs per hour until 8h p.i. In parallel, host transcriptional activity dropped down to 10-20%. While the combined effects of both phenomena dominated infection-induced changes in total RNA, extensive gene-specific transcriptional regulation was observable in chromatin-associated RNA. This was surprisingly concordant between WT HSV-1 and its {Delta}vhs mutant and at least in parts mediated by the embryonic transcription factor DUX4. Furthermore, both WT and {Delta}vhs infection induced strong transcriptional up-regulation of a small subset of genes. Most of these were either poorly or not at all expressed prior to infection but already primed by H3K4me3 histone marks at their promoters. Most interestingly, analysis of chromatin-associated RNA revealed vhs-nuclease-activity-dependent transcriptional down-regulation of at least 150 cellular genes, in particular of many genes encoding integrin adhesome and extracellular matrix components. This was accompanied by a vhs-dependent reduction in protein levels by 8h p.i. for many of these genes. In summary, our study provides a comprehensive picture of the molecular mechanisms that govern cellular RNA metabolism during the first 8h of lytic HSV-1 infection. Author SummaryThe HSV-1 virion host shut-off (vhs) protein efficiently cleaves both host and viral mRNAs in a translation-dependent manner. In this study, we model and quantify changes in vhs activity as well as the virus-induced global loss of host transcriptional activity during productive HSV-1 infection. In general, HSV-1-induced alterations in total RNA levels were found to be predominantly shaped by these two global processes rather than gene-specific regulation. In contrast, chromatin-associated RNA depicted gene-specific transcriptional changes. This revealed highly concordant transcriptional changes in WT and{Delta} vhs infection, confirmed DUX4 as a key transcriptional regulator in HSV-1 infection and depicted vhs-dependent, transcriptional down-regulation of the integrin adhesome and extracellular matrix. The latter explained some of the gene-specific effects previously attributed to vhs-mediated mRNA degradation and resulted in a concordant loss in protein levels by 8h p.i. for many of the respective genes.

microbiology↗

bioRxiv2020

Single Cell RNA-Sequencing-based Analysis of CD4+ T-Cell Subset-Specific Susceptibility to Transcriptional Modulation by HIV-1 Latency-Reversing Agents

Shock-and-kill is one of the most advanced, yet unrealized, concepts towards establishment of HIV-1 cure. Treatment with latency-reversing agents (LRAs), including histone deacetylase inhibitors (HDACis) exerting chromatin remodelling and gene expression reprogramming, combined with anti-retroviral therapy reactivates HIV-1 transcription in vitro, ex vivo and in vivo. However, HDACi treatment fails to significantly reduce the size of the viral reservoir in people living with HIV-1 (PLHIV). Here, by combining scRNA-seq and functional approaches, we characterised the HDACi treatment-imposed remodulation of CD4+ T-cells state and its consequences for HIV-1 latency reversal and the apparent resistance of HIV-1-reactivating cells to immune-mediated elimination. Exposure of CD4+ T-cells from three aviremic PLHIV with clinically applicable concentrations of Panobinostat markedly reduced the expression of genes mediating T-cell activation and IFN-driven antiviral immunity in a largely CD4+ T-cell subset-nonspecific manner, with exception of an PLHIV-specific exhausted CD4+ T-cell subpopulation. Altered transcriptomic profiles were accompanied by large refractoriness to peptide and IL-2/PHA stimulation, and to exogenous type I interferon, that would otherwise induce T-cell activation and expression of a plethora of antiviral genes, respectively. Type I interferon, when added to Panobinostat during HIV-1 reactivation, was unable to counteract HDACi-mediated inhibition of IFN signalling and failed to interfere with HIV-1 reactivation per se. However, it imposed a pre-budding block and boosted surface levels of HIV-1 Env on reactivating cells. Co-treatment with type I IFNs, most prominently IFN-{beta} and -14, sensitised HIV-1-reactivating cells for killing by NK cells through antibody-dependent cytotoxicity. Together, our study provides proof-of-concept of the benefit of combining a potent LRA with immunostimulatory molecules, such as type I IFNs, to reduce the resistance of HIV-1-reactivating T-cells to immune-mediated elimination to improve current shock-and-kill strategies.

microbiology↗

bioRxiv2020

Resolving fate and transcriptome of hematopoietic stem cell clones

Adult bone marrow harbors a mosaic of hematopoietic stem cell (HSC) clones of embryonic origin, and recent work suggests that such clones may have coherent lineage fates. To probe under physiological conditions whether HSC clones with different fates are transcriptionally distinct, we developed PolyloxExpress - a Cre recombinase-dependent DNA substrate for in situ barcoding that allows parallel readout of barcodes and transcriptomes in single cells. We describe differentiation-inactive, multilineage and lineage-restricted HSC clones, find that they reside in distinct regions of the transcriptional landscape of hematopoiesis, and identify corresponding gene signatures. All clone types contain proliferating HSCs, indicating that differentiation-inactive HSCs can undergo symmetric self-renewal. Our work establishes an approach for studying determinants of stem cell fate in vivo and provides molecular evidence for fate coherence of HSC clones.

immunology↗