Publications by authors named "Tobias Tekath"

7 Publications

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The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11.

Blood Adv 2021 Oct 12. Epub 2021 Oct 12.

Belgian Cancer Registry, Brussels, Belgium.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem-cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as TSLC1, Tumour Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid to myeloid ratio in bone marrow although not altering their multi-lineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM and CBL and mutations of ASXL1, SF3B1 and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.
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http://dx.doi.org/10.1182/bloodadvances.2021005311DOI Listing
October 2021

Single-cell RNA-seq unravels alterations of the human spermatogonial stem cell compartment in patients with impaired spermatogenesis.

Cell Rep Med 2021 Sep 9;2(9):100395. Epub 2021 Sep 9.

Centre of Reproductive Medicine and Andrology, University Hospital of Münster, 48149 Münster, Germany.

Despite the high incidence of male infertility, only 30% of infertile men receive a causative diagnosis. To explore the regulatory mechanisms governing human germ cell function in normal and impaired spermatogenesis (crypto), we performed single-cell RNA sequencing (>30,000 cells). We find major alterations in the crypto spermatogonial compartment with increased numbers of the most undifferentiated spermatogonia (PIWIL4). We also observe a transcriptional switch within the spermatogonial compartment driven by increased and prolonged expression of the transcription factor Intriguingly, the EGR4-regulated chromatin-associated transcriptional repressor is downregulated at transcriptional and protein levels. This is associated with changes in spermatogonial chromatin structure and fewer A spermatogonia, characterized by tightly compacted chromatin and serving as reserve stem cells. These findings suggest that crypto patients are disadvantaged, as fewer cells safeguard their germline's genetic integrity. These identified spermatogonial regulators will be highly interesting targets to uncover genetic causes of male infertility.
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http://dx.doi.org/10.1016/j.xcrm.2021.100395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484693PMC
September 2021

Differential transcript usage analysis of bulk and single-cell RNA-seq data with DTUrtle.

Bioinformatics 2021 Sep 1. Epub 2021 Sep 1.

Institute of Medical Informatics, Heidelberg University Hospital, Heidelberg, 69120, Germany.

Motivation: Each year, the number of published bulk and single-cell RNA-seq data sets is growing exponentially. Studies analyzing such data are commonly looking at gene-level differences, while the collected RNA-seq data inherently represents reads of transcript isoform sequences. Utilizing transcriptomic quantifiers, RNA-seq reads can be attributed to specific isoforms, allowing for analysis of transcript-level differences. A differential transcript usage (DTU) analysis is testing for proportional differences in a gene's transcript composition, and has been of rising interest for many research questions, such as analysis of differential splicing or cell type identification.

Results: We present the R package DTUrtle, the first DTU analysis workflow for both bulk and single-cell RNA-seq data sets, and the first package to conduct a 'classical' DTU analysis in a single-cell context. DTUrtle extends established statistical frameworks, offers various result aggregation and visualization options and a novel detection probability score for tagged-end data. It has been successfully applied to bulk and single-cell RNA-seq data of human and mouse, confirming and extending key results. Additionally, we present novel potential DTU applications like the identification of cell type specific transcript isoforms as biomarkers.

Availability: The R package DTUrtle is available at https://github.com/TobiTekath/DTUrtle with extensive vignettes and documentation at https://tobitekath.github.io/DTUrtle/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab629DOI Listing
September 2021

Whole-genome methylation analysis of testicular germ cells from cryptozoospermic men points to recurrent and functionally relevant DNA methylation changes.

Clin Epigenetics 2021 Aug 21;13(1):160. Epub 2021 Aug 21.

Institute of Human Genetics, University Hospital Essen, Essen, Germany.

Background: Several studies have reported an association between male infertility and aberrant sperm DNA methylation patterns, in particular in imprinted genes. In a recent investigation based on whole methylome and deep bisulfite sequencing, we have not found any evidence for such an association, but have demonstrated that somatic DNA contamination and genetic variation confound methylation studies in sperm of severely oligozoospermic men. To find out whether testicular germ cells (TGCs) of such patients might carry aberrant DNA methylation, we compared the TGC methylomes of four men with cryptozoospermia (CZ) and four men with obstructive azoospermia, who had normal spermatogenesis and served as controls (CTR).

Results: There was no difference in DNA methylation at the whole genome level or at imprinted regions between CZ and CTR samples. However, using stringent filters to identify group-specific methylation differences, we detected 271 differentially methylated regions (DMRs), 238 of which were hypermethylated in CZ (binominal test, p < 2.2 × 10). The DMRs were enriched for distal regulatory elements (p = 1.0 × 10) and associated with 132 genes, 61 of which are differentially expressed at various stages of spermatogenesis. Almost all of the 67 DMRs associated with the 61 genes (94%) are hypermethylated in CZ (63/67, p = 1.107 × 10). As judged by single-cell RNA sequencing, 13 DMR-associated genes, which are mainly expressed during meiosis and spermiogenesis, show a significantly different pattern of expression in CZ patients. In four of these genes, the promoter is hypermethylated in CZ men, which correlates with a lower expression level in these patients. In the other nine genes, eight of which downregulated in CZ, germ cell-specific enhancers may be affected.

Conclusions: We found that impaired spermatogenesis is associated with DNA methylation changes in testicular germ cells at functionally relevant regions of the genome. We hypothesize that the described DNA methylation changes may reflect or contribute to premature abortion of spermatogenesis and therefore not appear in the mature, motile sperm.
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http://dx.doi.org/10.1186/s13148-021-01144-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379757PMC
August 2021

Platelets orchestrate the resolution of pulmonary inflammation in mice by T reg cell repositioning and macrophage education.

J Exp Med 2021 07 20;218(7). Epub 2021 May 20.

Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.

Beyond hemostasis, platelets actively participate in immune cell recruitment and host defense, yet their potential in the resolution of inflammatory processes remains unknown. Here, we demonstrate that platelets are recruited into the lung together with neutrophils during the onset of inflammation and alongside regulatory T (T reg) cells during the resolution phase. This partnering dichotomy is regulated by differential adhesion molecule expression during resolution. Mechanistically, intravascular platelets form aggregates with T reg cells, a prerequisite for their recruitment into the lung. This interaction relies on platelet activation by sCD40L and platelet P-selectin binding to PSGL-1 on T reg cells. Physical platelet-T reg cell interactions are necessary to modulate the transcriptome and instruct T reg cells to release the anti-inflammatory mediators IL-10 and TGFβ. Notably, the presence of platelet-T reg cell aggregates in the lung was also required for macrophage transcriptional reprogramming, polarization toward an anti-inflammatory phenotype, and effective resolution of pulmonary inflammation. Thus, platelets partner with successive immune cell subsets to orchestrate both the initiation and resolution of inflammation.
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http://dx.doi.org/10.1084/jem.20201353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142284PMC
July 2021

Immunophenotyping in pemphigus reveals a T17/T17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production.

J Allergy Clin Immunol 2021 06 20;147(6):2358-2369. Epub 2020 Nov 20.

Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg, Germany.

Background: T2 cells were thought to be a pivotal factor for initiation of the autoimmune blistering disease pemphigus. However, the role of other T-cell subsets in pemphigus pathogenesis remained unclear.

Objective: We aimed to characterize the exact phenotype of T cells responsible for the development of pemphigus.

Methods: Whole transcriptome shotgun sequencing was performed to determine differential gene expression in pemphigus lesions and skin of healthy individuals. The cutaneous cytokine signature was further evaluated by real-time quantitative PCR. In peripheral blood, the distribution of T cell and folliclular helper (T) cell subsets was analyzed by flow cytometry. Finally, the capacity of T and T cell subsets to induce desmoglein (Dsg)-specific autoantibodies by memory B cells was evaluated in coculture experiments.

Results: Transcriptome analysis of skin samples identified an IL-17A-dominated immune signature in patients with pemphigus, and Kyoto Encyclopedia of Genes and Genomes pathway analysis confirmed the dominance of the IL-17A signaling pathway. Increased expression of IL17A and associated cytokines was also detected by real-time quantitative PCR comparing lesional with perilesional or healthy skin. Interestingly, utilization of flow cytometry showed that patients with active pemphigus had elevated levels of circulating IL-17 T17, T17, and T17.1 cells. Notably, levels of T17 and T17 cells correlated with levels of Dsg-specific CD19CD27 memory B cells, and patients with acute pemphigus showed higher levels of Dsg3-autoreactive T17 cells. Coculture experiments revealed T17 cells as primarily responsible for inducing Dsg-specific autoantibody production by B cells.

Conclusion: Our findings show that T17 cells are critically involved in the pathogenesis of pemphigus and offer novel targets for therapeutic intervention.
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http://dx.doi.org/10.1016/j.jaci.2020.11.008DOI Listing
June 2021

Computational exploration of cis-regulatory modules in rhythmic expression data using the "Exploration of Distinctive CREs and CRMs" (EDCC) and "CRM Network Generator" (CNG) programs.

PLoS One 2018 3;13(1):e0190421. Epub 2018 Jan 3.

RNA Biology and Molecular Physiology, Faculty of Biology, Bielefeld University, Bielefeld, Germany.

Understanding the effect of cis-regulatory elements (CRE) and clusters of CREs, which are called cis-regulatory modules (CRM), in eukaryotic gene expression is a challenge of computational biology. We developed two programs that allow simple, fast and reliable analysis of candidate CREs and CRMs that may affect specific gene expression and that determine positional features between individual CREs within a CRM. The first program, "Exploration of Distinctive CREs and CRMs" (EDCC), correlates candidate CREs and CRMs with specific gene expression patterns. For pairs of CREs, EDCC also determines positional preferences of the single CREs in relation to each other and to the transcriptional start site. The second program, "CRM Network Generator" (CNG), prioritizes these positional preferences using a neural network and thus allows unbiased rating of the positional preferences that were determined by EDCC. We tested these programs with data from a microarray study of circadian gene expression in Arabidopsis thaliana. Analyzing more than 1.5 million pairwise CRE combinations, we found 22 candidate combinations, of which several contained known clock promoter elements together with elements that had not been identified as relevant to circadian gene expression before. CNG analysis further identified positional preferences of these CRE pairs, hinting at positional information that may be relevant for circadian gene expression. Future wet lab experiments will have to determine which of these combinations confer daytime specific circadian gene expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190421PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752016PMC
February 2018
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