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55 Publications visible to you, out of a total of 55
On the Cooperation between Epigenetics and Transcription Factor Networks in the Specification of Tissue Stem Cells
LHA - Leipzig Health Atlas

Abstract (Expand)

It is generally accepted that epigenetic modifications, such as DNA and histone methylations, affect transcription and that a gene’s transcription feeds back on its epigenetic profile. Depending on the … epigenetic modification, positive and negative feedback loops have been described. Here, we study whether such interrelation are mandatory and how transcription factor networks affect it. We apply self-organizing map machine learning to a published data set on the specification and differentiation of murine intestinal stem cells in order to provide an integrative view of gene transcription and DNA, as well as histone methylation during this process. We show that, although gain/loss of H3K4me3 at a gene promoter is generally considered to be associated with its increased/decreased transcriptional activity, such an interrelation is not mandatory, i.e., changes of the modification level do not necessarily affect transcription. Similar considerations hold for H3K27me3. In addition, even strong changes in the transcription of a gene do not necessarily affect its H3K4me3 and H3K27me3 modification profile. We provide a mechanistic explanation of these phenomena that is based on a model of epigenetic regulation of transcription. Thereby, the analyzed data suggest a broad variance in gene specific regulation of histone methylation and support the assumption of an independent regulation of transcription by histone methylation and transcription factor networks. The results provide insights into basic principles of the specification of tissue stem cells and highlight open questions about a mechanistic modeling of this process.

Authors: T. Thalheim, Lydia Hopp, Hans Binder, G. Aust, J. Galle

Date Published: No date defined

Publication Type: Not specified

Multi-omics cartography of glioma heterogeneity
GGN - German Glioma Network

Abstract (Expand)

Molecular mechanisms of lower grade (II- III) diffuse gliomas (LGG) are still poorly understood, mainly because of their heterogeneity. They split into astrocytoma- (IDH-A) and oligodendro-glioma-like … (IDH-O) tumors both carrying mutations(s) at the Isocitrate dehydrogenase (IDH) gene and into IDH wild type (IDH-wt) gliomas of glioblastoma-resemblance. We generated de-tailed maps of the transcriptomes and DNA-methylomes revealing that cell functions divide into three major archeotypic hallmarks: (i) increased proliferation in IDH-wt and, to a less degree, IDH-O, (ii) increased inflammation in IDH-A and IDH-wt, and (iii) the loss of synaptic transmis-sion in all subtypes. Immunogenic properties of IDH-A are diverse partly resembling signatures observed in grade IV mesenchymal glioblastomas or in grade I pilocytic astrocytomas. We ana-lyzed details of coregulation between gene expression and DNA-methylation and of the immu-nogenic micro-environment presumably driving tumor development and treatment resistance. Our transcriptome and methylome maps support personalized, case-by-case views to decipher the heterogeneity of glioma states in terms of data portraits. Thereby molecular cartography provides a graphical coordinate system, which links gene-level information with glioma sub-types, their phenotypes and clinical context.

Authors: Hans Binder, Maria Schmidt, Lydia Hopp, Arsen Arakelyan, Henry Löffler-Wirth

Date Published: No date defined

Publication Type: Journal article

Human Diseases: brain glioma

Transcriptional states of CAR-T infusion relate to neurotoxicity - lessons from high-resolution single-cell SOM expression portraying.
imSAVAR - Immune safety avatar: nonclinical mimicking of the immune system effects of immunomodulatory therapies

Abstract (Expand)

Anti-CD19 CAR-T cell immunotherapy is a hopeful treatment option for patients with B cell lymphomas, however it copes with partly severe adverse effects like neurotoxicity. Single-cell resolved molecular … data sets in combination with clinical parametrization allow for comprehensive characterization of cellular subpopulations, their transcriptomic states, and their relation to the adverse effects. We here present a re-analysis of single-cell RNA sequencing data of 24 patients comprising more than 130,000 cells with focus on cellular states and their association to immune cell related neurotoxicity. For this, we developed a single-cell data portraying workflow to disentangle the transcriptional state space with single-cell resolution and its analysis in terms of modularly-composed cellular programs. We demonstrated capabilities of single-cell data portraying to disentangle transcriptional states using intuitive visualization, functional mining, molecular cell stratification, and variability analyses. Our analysis revealed that the T cell composition of the patient's infusion product as well as the spectrum of their transcriptional states of cells derived from patients with low ICANS grade do not markedly differ from those of cells from high ICANS patients, while the relative abundancies, particularly that of cycling cells, of LAG3-mediated exhaustion and of CAR positive cells, vary. Our study provides molecular details of the transcriptomic landscape with possible impact to overcome neurotoxicity.

Authors: H. Loeffler-Wirth, M. Rade, A. Arakelyan, M. Kreuz, M. Loeffler, U. Koehl, K. Reiche, H. Binder

Date Published: 17th Oct 2022

Publication Type: Journal article

The Leipzig Health Atlas-An Open Platform to Present, Archive, and Share Biomedical Data, Analyses, and Models Online.
LHA - Leipzig Health Atlas

Abstract (Expand)

BACKGROUND: Clinical trials, epidemiological studies, clinical registries, and other prospective research projects, together with patient care services, are main sources of data in the medical research … domain. They serve often as a basis for secondary research in evidence-based medicine, prediction models for disease, and its progression. This data are often neither sufficiently described nor accessible. Related models are often not accessible as a functional program tool for interested users from the health care and biomedical domains. OBJECTIVE: The interdisciplinary project Leipzig Health Atlas (LHA) was developed to close this gap. LHA is an online platform that serves as a sustainable archive providing medical data, metadata, models, and novel phenotypes from clinical trials, epidemiological studies, and other medical research projects. METHODS: Data, models, and phenotypes are described by semantically rich metadata. The platform prefers to share data and models presented in original publications but is also open for nonpublished data. LHA provides and associates unique permanent identifiers for each dataset and model. Hence, the platform can be used to share prepared, quality-assured datasets and models while they are referenced in publications. All managed data, models, and phenotypes in LHA follow the FAIR principles, with public availability or restricted access for specific user groups. RESULTS: The LHA platform is in productive mode (https://www.health-atlas.de/). It is already used by a variety of clinical trial and research groups and is becoming increasingly popular also in the biomedical community. LHA is an integral part of the forthcoming initiative building a national research data infrastructure for health in Germany.

Authors: T. Kirsten, F. A. Meineke, H. Loeffler-Wirth, C. Beger, A. Uciteli, S. Staubert, M. Lobe, R. Hansel, F. G. Rauscher, J. Schuster, T. Peschel, H. Herre, J. Wagner, S. Zachariae, C. Engel, M. Scholz, E. Rahm, H. Binder, M. Loeffler

Date Published: 3rd Aug 2022

Publication Type: Journal article

A Transcriptome-Wide Isoform Landscape of Melanocytic Nevi and Primary Melanomas Identifies Gene Isoforms Associated with Malignancy.
Leipzig Melanoma Studies, oBIG - omics Bioinformatics for Health

Abstract (Expand)

Genetic splice variants have become of central interest in recent years, as they play an important role in different cancers. Little is known about splice variants in melanoma. Here, we analyzed a … genome-wide transcriptomic dataset of benign melanocytic nevi and primary melanomas (n = 80) for the expression of specific splice variants. Using kallisto, a map for differentially expressed splice variants in melanoma vs. benign melanocytic nevi was generated. Among the top genes with differentially expressed splice variants were Ras-related in brain 6B (RAB6B), a member of the RAS family of GTPases, Macrophage Scavenger Receptor 1 (MSR1), Collagen Type XI Alpha 2 Chain (COLL11A2), and LY6/PLAUR Domain Containing 1 (LYPD1). The Gene Ontology terms of differentially expressed splice variants showed no enrichment for functional gene sets of melanoma vs. nevus lesions, but between type 1 (pigmentation type) and type 2 (immune response type) melanocytic lesions. A number of genes such as Checkpoint Kinase 1 (CHEK1) showed an association of mutational patterns and occurrence of splice variants in melanoma. Moreover, mutations in genes of the splicing machinery were common in both benign nevi and melanomas, suggesting a common mechanism starting early in melanoma development. Mutations in some of these genes of the splicing machinery, such as Serine and Arginine Rich Splicing Factor A3 and B3 (SF3A3, SF3B3), were significantly enriched in melanomas as compared to benign nevi. Taken together, a map of splice variants in melanoma is presented that shows a multitude of differentially expressed splice genes between benign nevi and primary melanomas. The underlying mechanisms may involve mutations in genes of the splicing machinery.

Authors: S. Hakobyan, H. Loeffler-Wirth, A. Arakelyan, H. Binder, M. Kunz

Date Published: 2nd Jul 2021

Publication Type: Journal article

The Human Blood Transcriptome in a Large Population Cohort and Its Relation to Aging and Health.
LIFE Adult, oBIG - omics Bioinformatics for Health

Abstract (Expand)

Background: The blood transcriptome is expected to provide a detailed picture of an organism's physiological state with potential outcomes for applications in medical diagnostics and molecular and … epidemiological research. We here present the analysis of blood specimens of 3,388 adult individuals, together with phenotype characteristics such as disease history, medication status, lifestyle factors, and body mass index (BMI). The size and heterogeneity of this data challenges analytics in terms of dimension reduction, knowledge mining, feature extraction, and data integration. Methods: Self-organizing maps (SOM)-machine learning was applied to study transcriptional states on a population-wide scale. This method permits a detailed description and visualization of the molecular heterogeneity of transcriptomes and of their association with different phenotypic features. Results: The diversity of transcriptomes is described by personalized SOM-portraits, which specify the samples in terms of modules of co-expressed genes of different functional context. We identified two major blood transcriptome types where type 1 was found more in men, the elderly, and overweight people and it upregulated genes associated with inflammation and increased heme metabolism, while type 2 was predominantly found in women, younger, and normal weight participants and it was associated with activated immune responses, transcriptional, ribosomal, mitochondrial, and telomere-maintenance cell-functions. We find a striking overlap of signatures shared by multiple diseases, aging, and obesity driven by an underlying common pattern, which was associated with the immune response and the increase of inflammatory processes. Conclusions: Machine learning applications for large and heterogeneous omics data provide a holistic view on the diversity of the human blood transcriptome. It provides a tool for comparative analyses of transcriptional signatures and of associated phenotypes in population studies and medical applications.

Authors: M. Schmidt, L. Hopp, A. Arakelyan, H. Kirsten, C. Engel, K. Wirkner, K. Krohn, R. Burkhardt, J. Thiery, M. Loeffler, H. Loeffler-Wirth, H. Binder

Date Published: 11th Mar 2021

Publication Type: Journal article

Deciphering the Transcriptomic Heterogeneity of Duodenal Coeliac Disease Biopsies.
LHA - Leipzig Health Atlas

Abstract (Expand)

Coeliac disease (CD) is a clinically heterogeneous autoimmune disease with variable presentation and progression triggered by gluten intake. Molecular or genetic factors contribute to disease heterogeneity, … but the reasons for different outcomes are poorly understood. Transcriptome studies of tissue biopsies from CD patients are scarce. Here, we present a high-resolution analysis of the transcriptomes extracted from duodenal biopsies of 24 children and adolescents with active CD and 21 individuals without CD but with intestinal afflictions as controls. The transcriptomes of CD patients divide into three groups-a mixed group presenting the control cases, and CD-low and CD-high groups referring to lower and higher levels of CD severity. Persistence of symptoms was weakly associated with subgroup, but the highest marsh stages were present in subgroup CD-high, together with the highest cell cycle rates as an indicator of virtually complete villous atrophy. Considerable variation in inflammation-level between subgroups was further deciphered into immune cell types using cell type de-convolution. Self-organizing maps portrayal was applied to provide high-resolution landscapes of the CD-transcriptome. We find asymmetric patterns of miRNA and long non-coding RNA and discuss the effect of epigenetic regulation. Expression of genes involved in interferon gamma signaling represent suitable markers to distinguish CD from non-CD cases. Multiple pathways overlay in CD biopsies in different ways, giving rise to heterogeneous transcriptional patterns, which potentially provide information about etiology and the course of the disease.

Authors: J. Wolf, E. Willscher, H. Loeffler-Wirth, M. Schmidt, G. Flemming, M. Zurek, H. H. Uhlig, N. Handel, H. Binder

Date Published: 4th Mar 2021

Publication Type: Journal article

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The Health Atlas - Local Data Hub/Leipzig is an alliance of medical ontologists, medical systems biologists and clinical trials groups to design and implement a multi-functional and quality-assured atlas. It provides models, data and metadata on specific use cases from medical research fields.

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