Biology subjects

Hausmann, M.

Publications and source records attributed to Hausmann, M..

5 recordsLinked to original sources

bioRxiv2025

TRIM24 preserves cardiomyocyte immune quiescence by repressing interferon/STAT signaling

Innate immune activation in cardiomyocytes is a key driver of inflammatory heart disease and heart failure progression, yet the mechanisms by which cardiomyocytes maintain transcriptional immune quiescence remain poorly understood. TRIM24, a multidomain chromatin reader implicated in cancer and inflammation, has not been previously studied in the heart. Here, we investigated whether TRIM24 regulates interferon/STAT-driven inflammatory programs and paracrine signaling in cardiomyocytes. Single-nucleus RNA sequencing revealed a pronounced downregulation of TRIM24 specifically in cardiomyocytes from human ischemic cardiomyopathy, a change not detected by bulk RNA-sequencing in either human or mouse myocardial infarction samples, likely due to masking by non-cardiomyocyte cell populations. Fractionated protein analysis further demonstrated that TRIM24 is enriched in cardiomyocyte nuclei. Functional studies in neonatal rat ventricular cardiomyocytes showed that TRIM24 represses interferon-stimulated and STAT-dependent genes, including Mx1, Irf7, and Ifit3. ChIP-Seq revealed TRIM24 occupancy at STAT-bound regulatory regions, suggesting cooperative suppression of inflammatory gene networks. Mechanistically, TRIM24 decreased Stat1a/b and Stat3 transcription, reduced protein abundance, and inhibited phosphorylation independently of proteasomal degradation; these effects were partially reversible by bromodomain inhibition. Functionally, TRIM24 overexpression dampened paracrine macrophage recruitment, whereas TRIM24 depletion amplified it. Collectively, these findings identify TRIM24 as a cardiomyocyte-enriched chromatin regulator that restrains STAT1/3 signaling and suppresses paracrine inflammatory activation. TRIM24 acts as a transcriptional safeguard of immune quiescence in the heart and represents a potential therapeutic target for limiting cardiac inflammation.

molecular biology↗

bioRxiv2025

Lamin B1 Safeguards the B Cell Genome and Shapes Lymphoma Outcome

Lamin B1 is a structural component of the nuclear lamina that participates in diverse cellular processes, including genome regulation and cellular senescence. During adaptive immune responses, B lymphocytes in germinal centres (GCs) undergo clonal expansion and programmed DNA damage at immunoglobulin loci, while simultaneously downregulating Lamin B1. Likewise, Lamin B1 downregulation has been observed in GC-derived lymphomas and myeloid malignancies, yet the functional consequences of Lamin B1 loss during B cell development remain poorly understood. Here, we used in vivo and in vitro B cell models of conditional hypomorphic expression of Lamin B1, which showed elevated DNA damage, altered chromatin accessibility, and disrupted transcriptional profiles. Using sBLISS (in situ labelling and sequencing of double-strand breaks), we identified non-random double-strand break hotspots in both mouse and human GC B cells, depleted of Lamin B1. These breaks are preferentially located near transcriptional start sites (TSSs) and regulatory elements that control translation and mRNA fate, implicating Lamin B1 in protecting fragile regulatory regions. Moreover, low LMNB1 expression correlated with poor clinical outcomes in patients with diffuse large B cell lymphoma (DLBCL). Together, this study reveals a crucial role for Lamin B1 in preserving genomic stability in B cells, underscoring its impact on the pathogenesis of B cell-derived malignancies.

cancer biology↗

bioRxiv2025

GPR68, a proton-sensing GPCR, mediates acid-induced visceral nociception

Background & AimsLocalised acidification from immune cell infiltration and heightened glycolysis contributes to colitis pathology by activating acid-sensing receptors such as GPR68, a proton-sensing GPCR expressed on immune and stromal cells. Single-cell RNAseq analysis revealed GPR68 is also expressed in colonic sensory neurons, prompting us to investigate its role in acid-induced colonic nociception. MethodsExpression of GPR68 in colonic nociceptors and tissue from people with colitis was confirmed by in silico analysis of our RNAseq databases. Its contribution to disease activity was assessed using the acute dextran sulphate sodium (DSS) model of colitis. Acid-evoked sensory signalling was evaluated via colonic afferent recordings and Ca{superscript 2} imaging in DRG neurons from wild-type and GPR68-/- mice, supported by pharmacological studies using Ogerin (a GPR68 positive allosteric modulator) and Ogremorphin (a GPR68 antagonist). ResultsRNAseq analysis showed GPR68 is robustly expressed in Trpv1 colonic nociceptors and upregulated in tissue from people with inflammatory bowel disease, consistent with reduced disease activity in DSS-treated GPR68-/- mice. Genetic deletion of GPR68 abolished colonic afferent responses to acid, which were also attenuated by Ogremorphin and enhanced by Ogerin. In Ca{superscript 2}-free buffer, DRG neurons from GPR68-/- mice or those pre-treated with Ogremorphin showed significantly reduced acid-evoked intracellular Ca{superscript 2} responses. By contrast the colonic afferent and DRG Ca2+ response (in Ca2+-containing buffer) to capsaicin was comparable between tissue from wild-type and GPR68-/- mice highlighting the involvement of divergent proton-dependent cellular signalling cascades. ConclusionsThese findings identify GPR68 as a key mediator of acid-induced colonic nociception and highlight its potential as a therapeutic target for the treatment of pain in colitis. SynopsisWe demonstrate that the proton-sensing receptor GPR68 mediates acid-induced signalling in colonic sensory neurons. Genetic and pharmacological modulation confirms GPR68s role in visceral nociception and supports its potential as a therapeutic target for pain management in colitis.

neuroscience↗

bioRxiv2024

Engineering a novel probiotic toolkit in Escherichia coli Nissle1917 for sensing and mitigating gut inflammatory diseases

Inflammatory Bowel Disease (IBD) is characterized by chronic intestinal inflammation with no cure and limited treatment options that often have systemic side effects. In this study, we developed a target-specific system to potentially treat IBD by engineering the probiotic bacterium Escherichia coli Nissle 1917 (EcN). Our modular system comprises three components: a transcription factor-based sensor (NorR) capable of detecting the inflammation biomarker nitric oxide, a type 1 hemolysin secretion system, and a therapeutic cargo consisting of a library of humanized anti-TNF nanobodies. Despite a reduction in sensitivity, our system demonstrated a concentration-dependent response to nitric oxide, successfully secreting functional nanobodies with binding affinities comparable to the commonly used drug Adalimumab, as confirmed by ELISA and in vitro assays. This newly validated nanobody library expands EcN therapeutic capabilities. The adopted secretion system, also characterized for the first time in EcN, can be further adapted as a platform for screening and purifying proteins of interest. Additionally, we provided a mathematical framework to assess critical parameters in engineering probiotic systems, including the production and diffusion of relevant molecules, bacterial colonization rates, and particle interactions. This integrated approach expands the synthetic biology toolbox for EcN-based therapies, providing novel parts, circuits, and a model for tunable responses at inflammatory hotspots. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/599326v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@173d556org.highwire.dtl.DTLVardef@1bb2ae1org.highwire.dtl.DTLVardef@fc1fcborg.highwire.dtl.DTLVardef@8b5f7f_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical Table of Contents. The engineered probiotic system: Inflamed intestinal cells release the inflammatory regulator TNF (depicted as red squares), which promotes inflammation through a positive feedback loop. Concurrently, these cells produce large amounts of nitric oxide (NO, represented by yellow circles) during inflammation. Our custom-engineered EcN biosensor can detect NO using a NorR-based sensor (in purple) and subsequently trigger the production of nanobodies (in turquoise). These nanobodies are then released into the extracellular environment via a specially engineered secretion system in the bacterial host (shown in dark blue). Once outside the cell, the nanobodies attach to TNF, effectively sequestering them and reducing inflammation. The graph at the bottom of this panel illustrates the general behavior of our system: nanobody production starts upon reaching a certain NO concentration threshold and continues in an NO-dependent fashion. As nanobodies are produced, they capture TNF, leading to a reduction in inflammation and a decrease in NO production. This decrease in NO then halts the nanobody production. SignificanceProbiotics can be engineered to detect and act upon extracellular disease indicators, optimizing therapeutic outcomes. Particularly, self-regulating sense-and-respond genetic circuits have the potential to enhance the accuracy, efficacy, and adaptability of treatment interventions. In this study, we developed and characterized a new integrated and modular toolkit that detects a gut inflammation biomarker, specifically nitric oxide, and responds to it in an inducible manner by secreting humanized nanobodies targeting the pro-inflammatory molecule TNF. We also develop a coarse-grained mathematical framework for modelling engineered probiotic activity in the gut. This novel system contributes to current efforts to develop new engineered probiotic systems and holds promise for inspiring new treatments for gut inflammation associated with various autoimmune diseases.

synthetic biology↗

bioRxiv2018

The oxysterol synthesizing enzyme CH25H contributes to the development of intestinal fibrosis

Intestinal fibrosis and stenosis are common complications of Crohns disease (CD), frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidized cholesterol derivatives, with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase (CH25H) converts cholesterol to 25-hydroxycholesterol (25-HC), which modulates immune responses and oxidative stress. In human intestinal samples from CD patients we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme using the sodium dextran sulfate (DSS)-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis.

immunology↗