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55 Publications visible to you, out of a total of 55
Teratogenic Rubella Virus Alters the Endodermal Differentiation Capacity of Human Induced Pluripotent Stem Cells.
LHA - Leipzig Health Atlas

Abstract (Expand)

The study of congenital virus infections in humans requires suitable ex vivo platforms for the species-specific events during embryonal development. A prominent example for these infections is rubella … virus (RV) which most commonly leads to defects in ear, heart, and eye development. We applied teratogenic RV to human induced pluripotent stem cells (iPSCs) followed by differentiation into cells of the three embryonic lineages (ecto-, meso-, and endoderm) as a cell culture model for blastocyst- and gastrulation-like stages. In the presence of RV, lineage-specific differentiation markers were expressed, indicating that lineage identity was maintained. However, portrait analysis of the transcriptomic expression signatures of all samples revealed that mock- and RV-infected endodermal cells were less related to each other than their ecto- and mesodermal counterparts. Markers for definitive endoderm were increased during RV infection. Profound alterations of the epigenetic landscape including the expression level of components of the chromatin remodeling complexes and an induction of type III interferons were found, especially after endodermal differentiation of RV-infected iPSCs. Moreover, the eye field transcription factors RAX and SIX3 and components of the gene set vasculogenesis were identified as dysregulated transcripts. Although iPSC morphology was maintained, the formation of embryoid bodies as three-dimensional cell aggregates and as such cellular adhesion capacity was impaired during RV infection. The correlation of the molecular alterations induced by RV during differentiation of iPSCs with the clinical signs of congenital rubella syndrome suggests mechanisms of viral impairment of human development.

Authors: N. C. Bilz, E. Willscher, H. Binder, J. Bohnke, M. L. Stanifer, D. Hubner, S. Boulant, U. G. Liebert, C. Claus

Date Published: 10th Aug 2019

Publication Type: Not specified

Population Levels Assessment of the Distribution of Disease-Associated Variants With Emphasis on Armenians - A Machine Learning Approach.
LHA - Leipzig Health Atlas, oBIG - omics Bioinformatics for Health

Abstract (Expand)

Background: During the last decades a number of genome-wide association studies (GWASs) has identified numerous single nucleotide polymorphisms (SNPs) associated with different complex diseases. However, … associations reported in one population are often conflicting and did not replicate when studied in other populations. One of the reasons could be that most GWAS employ a case-control design in one or a limited number of populations, but little attention was paid to the global distribution of disease-associated alleles across different populations. Moreover, the majority of GWAS have been performed on selected European, African, and Chinese populations and the considerable number of populations remains understudied. Aim: We have investigated the global distribution of so far discovered disease-associated SNPs across worldwide populations of different ancestry and geographical regions with a special focus on the understudied population of Armenians. Data and Methods: We have used genotyping data from the Human Genome Diversity Project and of Armenian population and combined them with disease-associated SNP data taken from public repositories leading to a final dataset of 44,234 markers. Their frequency distribution across 1039 individuals from 53 populations was analyzed using self-organizing maps (SOM) machine learning. Our SOM portrayal approach reduces data dimensionality, clusters SNPs with similar frequency profiles and provides two-dimensional data images which enable visual evaluation of disease-associated SNPs landscapes among human populations. Results: We find that populations from Africa, Oceania, and America show specific patterns of minor allele frequencies of disease-associated SNPs, while populations from Europe, Middle East, Central South Asia, and Armenia mostly share similar patterns. Importantly, different sets of SNPs associated with common polygenic diseases, such as cancer, diabetes, neurodegeneration in populations from different geographic regions. Armenians are characterized by a set of SNPs that are distinct from other populations from the neighboring geographical regions. Conclusion: Genetic associations of diseases considerably vary across populations which necessitates health-related genotyping efforts especially for so far understudied populations. SOM portrayal represents novel promising methods in population genetic research with special strength in visualization-based comparison of SNP data.

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

Date Published: 21st May 2019

Publication Type: Journal article

A modular transcriptome map of mature B cell lymphomas.
GLA - German Lymphoma Alliance, MMML-MYC-SYS, oBIG - omics Bioinformatics for Health

Abstract (Expand)

BACKGROUND: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic … phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. METHODS: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. RESULTS: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. CONCLUSIONS: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.

Authors: H. Loeffler-Wirth, M. Kreuz, L. Hopp, A. Arakelyan, A. Haake, S. B. Cogliatti, A. C. Feller, M. L. Hansmann, D. Lenze, P. Moller, H. K. Muller-Hermelink, E. Fortenbacher, E. Willscher, G. Ott, A. Rosenwald, C. Pott, C. Schwaenen, H. Trautmann, S. Wessendorf, H. Stein, M. Szczepanowski, L. Trumper, M. Hummel, W. Klapper, R. Siebert, M. Loeffler, H. Binder

Date Published: 30th Apr 2019

Publication Type: Not specified

Human Diseases: B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Burkitt lymphoma

DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development.
GGN - German Glioma Network

Abstract (Expand)

BACKGROUND: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread … genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. METHODS: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. RESULTS: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related 'keratinization' methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. CONCLUSIONS: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment.

Authors: H. Binder, E. Willscher, H. Loeffler-Wirth, L. Hopp, D. T. W. Jones, S. M. Pfister, M. Kreuz, D. Gramatzki, E. Fortenbacher, B. Hentschel, M. Tatagiba, U. Herrlinger, H. Vatter, J. Matschke, M. Westphal, D. Krex, G. Schackert, J. C. Tonn, U. Schlegel, H. J. Steiger, W. Wick, R. G. Weber, M. Weller, M. Loeffler

Date Published: 25th Apr 2019

Publication Type: Not specified

Human Diseases: brain glioma

Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma.
MMML - Molecular mechanisms in malignant lymphoma

Abstract (Expand)

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. … Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.

Authors: C. Lopez, K. Kleinheinz, S. M. Aukema, M. Rohde, S. H. Bernhart, D. Hubschmann, R. Wagener, U. H. Toprak, F. Raimondi, M. Kreuz, S. M. Waszak, Z. Huang, L. Sieverling, N. Paramasivam, J. Seufert, S. Sungalee, R. B. Russell, J. Bausinger, H. Kretzmer, O. Ammerpohl, A. K. Bergmann, H. Binder, A. Borkhardt, B. Brors, A. Claviez, G. Doose, L. Feuerbach, A. Haake, M. L. Hansmann, J. Hoell, M. Hummel, J. O. Korbel, C. Lawerenz, D. Lenze, B. Radlwimmer, J. Richter, P. Rosenstiel, A. Rosenwald, M. B. Schilhabel, H. Stein, S. Stilgenbauer, P. F. Stadler, M. Szczepanowski, M. A. Weniger, M. Zapatka, R. Eils, P. Lichter, M. Loeffler, P. Moller, L. Trumper, W. Klapper, S. Hoffmann, R. Kuppers, B. Burkhardt, M. Schlesner, R. Siebert

Date Published: 29th Mar 2019

Publication Type: Not specified

Human Diseases: lymphoma, Burkitt lymphoma

Longitudinal anthropometry of children and adolescents using 3D-body scanning.
LIFE - Leipzig Research Center for Civilization Diseases, LIFE Child

Abstract (Expand)

3D-body scanning anthropometry is a suitable method for characterization of physiological development of children and adolescents, and for understanding onset and progression of disorders like overweight … and obesity. Here we present a novel body typing approach to describe and to interpret longitudinal 3D-body scanning data of more than 800 children and adolescents measured in up to four follow-ups in intervals of 1 year, referring to an age range between 6 and 18 years. We analyzed transitions between body types assigned to lower-, normal- and overweight participants upon development of children and adolescents. We found a virtually parallel development of the body types with only a few transitions between them. Body types of children and adolescents tend to conserve their weight category. 3D body scanning anthropometry in combination with body typing constitutes a novel option to investigate onset and progression of obesity in children.

Authors: H. Loeffler-Wirth, M. Vogel, T. Kirsten, F. Glock, T. Poulain, A. Korner, M. Loeffler, W. Kiess, H. Binder

Date Published: 14th Sep 2018

Publication Type: Not specified

Human Diseases: obesity

Footprints of Sepsis Framed Within Community Acquired Pneumonia in the Blood Transcriptome.
CAPSys - Footprints of Sepsis Framed Within Community Acquired Pneumonia in the Blood Transcriptome, oBIG - omics Bioinformatics for Health

Abstract (Expand)

We analyzed the blood transcriptome of sepsis framed within community-acquired pneumonia (CAP) and characterized its molecular and cellular heterogeneity in terms of functional modules of co-regulated … genes with impact for the underlying pathophysiological mechanisms. Our results showed that CAP severity is associated with immune suppression owing to T-cell exhaustion and HLA and chemokine receptor deactivation, endotoxin tolerance, macrophage polarization, and metabolic conversion from oxidative phosphorylation to glycolysis. We also found footprints of host's response to viruses and bacteria, altered levels of mRNA from erythrocytes and platelets indicating coagulopathy that parallel severity of sepsis and survival. Finally, our data demonstrated chromatin re-modeling associated with extensive transcriptional deregulation of chromatin modifying enzymes, which suggests the extensive changes of DNA methylation with potential impact for marker selection and functional characterization. Based on the molecular footprints identified, we propose a novel stratification of CAP cases into six groups differing in the transcriptomic scores of CAP severity, interferon response, and erythrocyte mRNA expression with impact for prognosis. Our analysis increases the resolution of transcriptomic footprints of CAP and reveals opportunities for selecting sets of transcriptomic markers with impact for translation of omics research in terms of patient stratification schemes and sets of signature genes.

Authors: L. Hopp, H. Loeffler-Wirth, L. Nersisyan, A. Arakelyan, H. Binder

Date Published: 2nd Aug 2018

Publication Type: Not specified

Human Diseases: disease by infectious agent, pneumonia

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