Biology subjects

Rauch, A.

Publications and source records attributed to Rauch, A..

12 recordsLinked to original sources

bioRxiv2026

Glucocorticoid signalling exerts distinct lineage-permissive and dose-dependent disruptive actions during human osteoblast differentiation

At physiological levels glucocorticoid (GC) signalling within the osteoblast lineage has been proposed to be required for skeletal homeostasis, whereas supraphysiological activation supresses bone formation and causes bone loss. While these observations suggest that GC exert dose- and context-dependent effects, the molecular mechanisms underlying these opposing actions remain unresolved. Here we systematically dissected the receptor-, lineage-, and concentration-dependent effects of GC signalling on human bone marrow stromal cell (BMSC) differentiation using integrated transcriptional, epigenomic, and functional analyses. Our findings suggest that GC opposing effects are not simply due to a GR dose-response but instead reflect distinct context- and concentration-dependent modes of action. During early BMSC differentiation, the cellular context induced GR-dependent licensing of lineage-specific gene and enhancer programs. The adverse effects of high-dose GC developed over time and could not be predicted from the early transcriptional response. We found that high-dose GC caused osteoblast maturation arrest, accompanied with a cellular stress response sustained by myeloid zinc finger 1 (MZF1) also identified as an endogenous inhibitor of osteoblast differentiation.

molecular biology↗

bioRxiv2025

Transcriptional plasticity of stromal cells amplifies their differentiation efficiency in vitro

Human bone marrow-derived stromal cells (also termed mesenchymal stem cell -MSCs) are progenitors capable of differentiating into bone forming osteoblasts and fat storing adipocytes. Due to the loss of bone mass being associated with increased marrow fat, trans-differentiation of osteoblasts into adipocytes been hypothesized as a contributor to osteoporotic bone loss and fragility. Reprogramming of transcriptional networks is a prerequisite for cellular differentiation, however, to which extent cell-type specific transcriptional networks modulate cellular plasticity within stromal cells remains unknown. In this study we performed gene expression analysis at bulk and single cell level in stromal cells being repeatedly exposed to osteogenic and adipogenic inducers in vitro. Surprisingly, cell type specific gene networks are not suppressive but instead promoting to obtain an opposing phenotype, e.g., enhanced osteoblast differentiation of adipogenic pre-stimulated stromal cells compared to undifferentiated ones. Mechanistically, lineage-selective genes with enhanced response upon interconversion are primed in the stem cell state and obtain modest activity levels during exposure to opposing lineage conditions. Finally, the presence of cells simultaneously showing an osteogenic and adipogenic phenotype highlighting a strong molecular plasticity of transcriptional networks in stromal cells. These observations provide a strong molecular support for the notion of not only progenitor specification but also the plasticity of differentiated cells contributing to the balance of bone mass and marrow fat content. SummaryWe provide mechanistic evidence, that cells with established lineage-selective gene programs are more vulnerable to obtain gene signatures and phenotypes of opposing lineages, building ground for trans-differentiation between osteoblasts and adipocytes being a coordinated process rather than random and misdirected.

cell biology↗

bioRxiv2025

CRISPR/Cas9-mediated generation of two isogenic CEP290-mutated iPSC lines

CEP290 is an important human disease gene, as mutations are implicated in a broad spectrum of autosomal recessive ciliopathies, including Leber congenital amaurosis and Joubert, Meckel, Senior-LOken or Bardet Biedl syndromes. To create isogenic mutant human induced pluripotent stem cell (hiPSC) lines for disease modeling, we employed CRISPR/Cas9 to introduce disease-relevant mutations into the control hiPSC line HMGU1 (ISFi001-A). Thorough characterization of the lines, including the effect of the mutation at the mRNA and protein level, shows that these CEP290-mutant lines provide a useful resource for studying ciliopathy disease mechanisms and cilia biology through differentiation into diverse cell types and organoids.

developmental biology↗

bioRxiv2024

The XbnAb Cohort: 304 people with broadly neutralizing antibody activity to HIV-1

Broadly neutralizing antibodies (bnAbs) recognizing a diversity of HIV-1 strains are widely thought to be essential for an HIV-1 vaccine. Extensive knowledge on bnAbs has been gained from studying natural HIV infection by following bnAb evolution in individual people with HIV (PWH). However, it remains essential to increase knowledge of bnAb responses in large PWH cohorts to assess the feasibility of inducing bnAb activity by vaccination. To allow systematic analysis, we created the XbnAb cohort, a large bnAb-inducer cohort selected by screening plasma of PWH enrolled in the Swiss HIV Cohort Study (SHCS) and the Zurich Primary HIV Infection Study (ZPHI). The XbnAb cohort represents a retrospective, biobank-based cohort comprising data of 305 PWH who developed bnAb activity during HIV-1 infection. Here, we report on the characteristics of the XbnAb cohort and its potential for HIV vaccine research.

immunology↗

bioRxiv2022

GIP receptor reduces osteoclast activity and improves osteoblast survival by activating multiple signaling pathways

Bone is a dynamic tissue that is remodeled throughout life by bone resorbing osteoclasts and bone forming osteoblasts, to adapt to physiological or mechanical demands. These processes are impaired in osteoporosis, and understanding how bone remodeling is regulated could improve anti-osteoporotic treatments. Clinical investigations show that short-term treatment with glucose-dependent insulinotropic polypeptide (GIP) acutely decreases serum markers of bone resorption and may increase bone formation. However, evidence for direct effects of GIP intracellular signaling and functions in mature human osteoclasts and osteoblasts have not been investigated. We report that the GIP receptor (GIPR) is robustly expressed in mature human osteoclasts. Exposure of osteoclasts to GIP inhibits osteoclastogenesis, delays bone resorption, and increases osteoclast apoptosis by acting upon multiple signaling pathways (cAMP, Src, Akt, calcium, p38) to impair nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) and nuclear factor-{kappa}B (NF{kappa}B). Human osteoblasts also express GIPR, and GIP improves osteoblast survival via cAMP and Akt-mediated pathways. GIP treatment of co-cultures of osteoclasts and osteoblasts also decreased bone resorption. Antagonizing GIPR with GIP(3-30)NH2 abolished the effects of GIP on osteoclasts and osteoblasts. This study demonstrates that GIP inhibits bone resorption and improves survival of human osteoblasts, which could increase bone mass and strength, supporting clinical investigations of the effect of GIP on bone. Moreover, this study demonstrates that GIPR agonism could be beneficial in the treatment of disorders of bone remodeling, such as osteoporosis. One-sentence SummaryGIP acts directly on bone cells to regulate bone remodeling

cell biology↗

bioRxiv2022

Anti-chemokine antibodies after SARS-CoV-2 infection correlate with favorable disease course

Infection by SARS-CoV-2 leads to diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse COVID-19 outcomes. Instead, we discovered that antibodies against specific chemokines are omnipresent after COVID-19, associated with favorable disease, and predictive of lack of long COVID symptoms at one year post infection. Anti-chemokine antibodies are present also in HIV-1 infection and autoimmune disorders, but they target different chemokines than those in COVID-19. Monoclonal antibodies derived from COVID- 19 convalescents that bind to the chemokine N-loop impair cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising anti-chemokine antibodies associated with favorable COVID-19 may be beneficial by modulating the inflammatory response and thus bear therapeutic potential. One-Sentence SummaryNaturally arising anti-chemokine antibodies associate with favorable COVID-19 and predict lack of long COVID.

immunology↗

bioRxiv2022

The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype

Variant of concern (VOC) Omicron-BA1 has achieved global predominance in early 2022. Therefore, surveillance and comprehensive characterization of Omicron-BA.1 in advanced primary cell culture systems and multiple animal models is urgently needed. Here, we characterized Omicron-BA.1 and recombinant Omicron-BA.1 spike gene mutants in comparison with VOC Delta in well-differentiated primary human nasal and bronchial epithelial cells in vitro, followed by in vivo fitness characterization in naive hamsters, ferrets and hACE2-expressing mice, and in immunized hACE2-mice. We demonstrate a spike-mediated enhancement of early replication of Omicron-BA.1 in nasal epithelial cultures, but limited replication in bronchial epithelial cultures. In Syrian hamsters, Delta showed dominance over Omicron-BA.1 and in ferrets, Omicron-BA.1 infection was abortive. In mice expressing the authentic hACE2-receptor, Delta and a Delta spike clone also showed dominance over Omicron-BA.1 and an Omicron-BA.1 spike clone, respectively. Interestingly, in naive K18-hACE2 mice, we observed Delta spike-mediated increased replication and pathogenicity and Omicron-BA.1 spike-mediated reduced replication and pathogenicity, suggesting that the spike gene is a major determinant of both Delta and Omicron-BA.1 replication and pathogenicity. Finally, the Omicron-BA.1 spike clone was less well controlled by mRNA-vaccination in K18-hACE2-mice and became more competitive compared to the progenitor and Delta spike clones, suggesting that spike gene-mediated immune evasion is another important factor that led to Omicron-BA.1 dominance.

microbiology↗

bioRxiv2021

Quantifying the impact of gut microbiota on inflammation and hypertensive organ damage

AimsHypertension (HTN) can lead to heart and kidney damage. The gut microbiota has been linked to HTN, although it is difficult to estimate its significance due to the variety of other features known to influence HTN. In the present study, we used germ-free (GF) and colonized (COL) littermate mice to quantify the impact of microbial colonization on organ damage in HTN. Methods and resultsFour-week-old male GF C57BL/6J littermates were randomized to remain GF or receive microbial colonization. HTN was induced by subcutaneous infusion with angiotensin (Ang) II (1.44mg/kg/d) and 1% NaCl in the drinking water; sham-treated mice served as control. Renal damage was exacerbated in GF mice, whereas cardiac damage was more comparable between COL and GF, suggesting that the kidney is more sensitive to microbial influence. Multivariate analysis revealed a larger effect of HTN in GF mice. Serum metabolomics demonstrated that the colonization status influences circulating metabolites relevant to HTN. Importantly, GF mice were deficient in anti-inflammatory fecal short-chain fatty acids (SCFA). Flow cytometry showed that the microbiome has an impact on the induction of anti-hypertensive myeloid-derived suppressor cells and pro-inflammatory Th17 cells in HTN. In vitro inducibility of Th17 cells was significantly higher for cells isolated from GF than conventionally raised mice. ConclusionsMicrobial colonization status of mice had potent effects on their phenotypic response to a hypertensive stimulus, and the kidney is a highly microbiota-susceptible target organ in HTN. The magnitude of the pathogenic response in GF mice underscores the role of the microbiome in mediating inflammation in HTN. Translation PerspectiveTo assess the potential of microbiota-targeted interventions to prevent organ damage in hypertension, an accurate quantification of microbial influence is necessary. We provide evidence that the development of hypertensive organ damage is dependent on colonization status and suggest that a healthy microbiota provides anti-hypertensive immune and metabolic signals to the host. In the absence of normal symbiotic host-microbiome interactions, hypertensive damage to the kidney in particular is exacerbated. We suggest that hypertensive patients experiencing perturbations to the microbiota, which are common in CVD, may be at a greater risk for target-organ damage than those with a healthy microbiome.

microbiology↗

bioRxiv2019

Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as Loss-of-Function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila Melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

genetics↗

bioRxiv2019

Prenatal diagnosis of HNF1B-associated renal cysts: Need to differentiate intragenic variants from 17q12 microdeletion syndrome?

ObjectiveLarge deletions of chromosome 17q12 (17q12DS) or intragenic variants in HNF1B are associated with variable developmental, endocrine and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe pre- and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to previous studies.\n\nMethodsPrenatal sequencing and postnatal chromosomal microarray analysis was performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants.\n\nResultsIn a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA binding domain, a mutational hotspot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions of varying size. Literature screening revealed highly variable reporting of HNF1B-associated clinical traits. Overall, developmental delay was more frequent in 17q12DS carriers, although both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum.\n\nConclusionsWe highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants is necessary for a more accurate risk quantification of pre- and postnatal clinical features, improving genetic counseling and prenatal decision-making.

genetics↗

bioRxiv2018

Need for high-resolution Genetic Analysis in iPSC: Results and Lessons from the ForIPS Consortium

Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines. In the majority, somatic copy number variants (CNVs) were identified. A subset with available matched donor DNA was selected for comparative exome sequencing. We identified single nucleotide variants (SNVs) at different allelic frequencies in each clone with high variability in mutational load. Low frequencies of variants in parental fibroblasts highlight the importance of germline samples. Somatic variant number was independent from reprogramming, cell type and passage. Comparison with disease genes and prediction scores suggest biological relevance for some variants. We show that high-throughput sequencing has value beyond SNV detection and the requirement to individually evaluate each clone.

genomics↗

bioRxiv2017

Dissecting HIV Virulence: Heritability Of Setpoint Viral Load, CD4+ T Cell Decline And Per-Parasite Pathogenicity

Pathogen strains may differ in virulence because they attain different loads in their hosts, or because they induce different disease-causing mechanisms independent of their load. In evolutionary ecology, the latter is referred to as \"per-parasite pathogenicity\". Using viral load and CD4+ T cell measures from 2014 HIV-1 subtype B infected individuals enrolled in the Swiss HIV Cohort Study, we investigated if virulence -- measured as the rate of decline of CD4+ T cells -- and per-parasite pathogenicity are heritable from donor to recipient. We estimated heritability by donor-recipient regressions applied to 196 previously identified transmission pairs, and by phylogenetic mixed models applied to a phylogenetic tree inferred from HIV pol sequences. Regressing the CD4+ T cell declines and per-parasite pathogenicities of the transmission pairs did not yield heritability estimates significantly different from zero. With the phylogenetic mixed model, however, our best estimate for the heritability of the CD4+ T cell decline is 17% (5%-30%), and that of the per-parasite pathogenicity is 17% (4%-29%). Further, we confirm that the set-point viral load is heritable, and estimate a heritability of 29% (12%-46%). Interestingly, the pattern of evolution of all these traits differs significantly from neutrality, and is most consistent with stabilizing selection for the set-point viral load, and with directional selection for the CD4+ T cell decline and the per-parasite pathogenicity. Our analysis shows that the viral genetype affects virulence mainly by modulating the per-parasite pathogenicity, while the indirect effect via the set-point viral load is minor.

evolutionary biology↗