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4 Publications visible to you, out of a total of 4
The lung microbiome regulates brain autoimmunity.

Abstract (Expand)

Lung infections and smoking are risk factors for multiple sclerosis, a T-cell-mediated autoimmune disease of the central nervous system(1). In addition, the lung serves as a niche for the disease-inducing … T cells for long-term survival and for maturation into migration-competent effector T cells(2). Why the lung tissue in particular has such an important role in an autoimmune disease of the brain is not yet known. Here we detected a tight interconnection between the lung microbiota and the immune reactivity of the brain. A dysregulation in the lung microbiome significantly influenced the susceptibility of rats to developing autoimmune disease of the central nervous system. Shifting the microbiota towards lipopolysaccharide-enriched phyla by local treatment with neomycin induced a type-I-interferon-primed state in brain-resident microglial cells. Their responsiveness towards autoimmune-dominated stimulation by type II interferons was impaired, which led to decreased proinflammatory response, immune cell recruitment and clinical signs. Suppressing lipopolysaccharide-producing lung phyla with polymyxin B led to disease aggravation, whereas addition of lipopolysaccharide-enriched phyla or lipopolysaccharide recapitulated the neomycin effect. Our data demonstrate the existence of a lung-brain axis in which the pulmonary microbiome regulates the immune reactivity of the central nervous tissue and thereby influences its susceptibility to autoimmune disease development.

Authors: L. Hosang, R. C. Canals, F. J. van der Flier, J. Hollensteiner, R. Daniel, A. Flugel, F. Odoardi

Date Published: 25th Feb 2022

Publication Type: Journal

Biallelic variants in YRDC cause a developmental disorder with progeroid features.

Abstract (Expand)

The highly conserved YrdC domain-containing protein (YRDC) interacts with the well-described KEOPS complex, regulating specific tRNA modifications to ensure accurate protein synthesis. Previous studies … have linked the KEOPS complex to a role in promoting telomere maintenance and controlling genome integrity. Here, we report on a newborn with a severe neonatal progeroid phenotype including generalized loss of subcutaneous fat, microcephaly, growth retardation, wrinkled skin, renal failure, and premature death at the age of 12 days. By trio whole-exome sequencing, we identified a novel homozygous missense mutation, c.662T > C, in YRDC affecting an evolutionary highly conserved amino acid (p.Ile221Thr). Functional characterization of patient-derived dermal fibroblasts revealed that this mutation impairs YRDC function and consequently results in reduced t(6)A modifications of tRNAs. Furthermore, we established and performed a novel and highly sensitive 3-D Q-FISH analysis based on single-telomere detection to investigate the impact of YRDC on telomere maintenance. This analysis revealed significant telomere shortening in YRDC-mutant cells. Moreover, single-cell RNA sequencing analysis of YRDC-mutant fibroblasts revealed significant transcriptome-wide changes in gene expression, specifically enriched for genes associated with processes involved in DNA repair. We next examined the DNA damage response of patient's dermal fibroblasts and detected an increased susceptibility to genotoxic agents and a global DNA double-strand break repair defect. Thus, our data suggest that YRDC may affect the maintenance of genomic stability. Together, our findings indicate that biallelic variants in YRDC result in a developmental disorder with progeroid features and might be linked to increased genomic instability and telomere shortening.

Authors: J. Schmidt, J. Goergens, T. Pochechueva, A. Kotter, N. Schwenzer, M. Sitte, G. Werner, J. Altmuller, H. Thiele, P. Nurnberg, J. Isensee, Y. Li, C. Muller, B. Leube, H. C. Reinhardt, T. Hucho, G. Salinas, M. Helm, R. D. Jachimowicz, D. Wieczorek, T. Kohl, S. E. Lehnart, G. Yigit, B. Wollnik

Date Published: 22nd Sep 2021

Publication Type: Journal

Caveolin3 Stabilizes McT1-Mediated Lactate/Proton Transport in Cardiomyocytes.

Abstract

[Figure: see text].

Authors: J. Peper, D. Kownatzki-Danger, G. Weninger, F. Seibertz, J. R. D. Pronto, H. Sutanto, D. Pacheu-Grau, R. Hindmarsh, S. Brandenburg, T. Kohl, G. Hasenfuss, M. Gotthardt, E. A. Rog-Zielinska, B. Wollnik, P. Rehling, H. Urlaub, J. Wegener, J. Heijman, N. Voigt, L. Cyganek, C. Lenz, S. E. Lehnart

Date Published: 19th Mar 2021

Publication Type: Journal

A context-specific cardiac beta-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart.

Abstract (Expand)

Chromatin remodelling precedes transcriptional and structural changes in heart failure. A body of work suggests roles for the developmental Wnt signalling pathway in cardiac remodelling. Hitherto, there … is no evidence supporting a direct role of Wnt nuclear components in regulating chromatin landscapes in this process. We show that transcriptionally active, nuclear, phosphorylated(p)Ser675-beta-catenin and TCF7L2 are upregulated in diseased murine and human cardiac ventricles. We report that inducible cardiomyocytes (CM)-specific pSer675-beta-catenin accumulation mimics the disease situation by triggering TCF7L2 expression. This enhances active chromatin, characterized by increased H3K27ac and TCF7L2 occupancies to cardiac developmental and remodelling genes in vivo. Accordingly, transcriptomic analysis of beta-catenin stabilized hearts shows a strong recapitulation of cardiac developmental processes like cell cycling and cytoskeletal remodelling. Mechanistically, TCF7L2 co-occupies distal genomic regions with cardiac transcription factors NKX2-5 and GATA4 in stabilized-beta-catenin hearts. Validation assays revealed a previously unrecognized function of GATA4 as a cardiac repressor of the TCF7L2/beta-catenin complex in vivo, thereby defining a transcriptional switch controlling disease progression. Conversely, preventing beta-catenin activation post-pressure-overload results in a downregulation of these novel TCF7L2-targets and rescues cardiac function. Thus, we present a novel role for TCF7L2/beta-catenin in CMs-specific chromatin modulation, which could be exploited for manipulating the ubiquitous Wnt pathway.

Authors: L. M. Iyer, S. Nagarajan, M. Woelfer, E. Schoger, S. Khadjeh, M. P. Zafiriou, V. Kari, J. Herting, S. T. Pang, T. Weber, F. S. Rathjens, T. H. Fischer, K. Toischer, G. Hasenfuss, C. Noack, S. A. Johnsen, L. C. Zelarayan

Date Published: 6th Apr 2018

Publication Type: Journal

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