Combined SOM-portrayal of gene expression and DNA methylation landscapes disentangles modes of epigenetic regulation in glioblastoma.
GGN - German Glioma Network

Abstract (Expand)

AIM: We present here a novel method that enables unraveling the interplay between gene expression and DNA methylation in complex diseases such as cancer. MATERIALS & METHODS: The method is based … on self-organizing maps and allows for analysis of data landscapes from 'governed by methylation' to 'governed by expression'. RESULTS: We identified regulatory modules of coexpressed and comethylated genes in high-grade gliomas: two modes are governed by genes hypermethylated and underexpressed in IDH-mutated cases, while two other modes reflect immune and stromal signatures in the classical and mesenchymal subtypes. A fifth mode with proneural characteristics comprises genes of repressed and poised chromatin states active in healthy brain. Two additional modes enrich genes either in active or repressed chromatin states. CONCLUSION: The method disentangles the interplay between gene expression and methylation. It has the potential to integrate also mutation and copy number data and to apply to large sample cohorts.

Authors: L. Hopp, H. Loffler-Wirth, J. Galle, H. Binder

Date Published: 12th Jun 2018

Publication Type: Not specified

Human Diseases: glioblastoma multiforme

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

Function Shapes Content: DNA-Methylation Marker Genes and their Impact for Molecular Mechanisms of Glioma
GGN - German Glioma Network

Abstract (Expand)

Glioma is a clinically and biologically diverse disease. It challenges diagnosis and prognosis due to its molecular heterogeneity and diverse regimes of biological dysfunctions which are driven by … genetic and epigenetic mechanisms. We discover the functional impact of sets of DNA methylation marker genes in the context of brain cancer subtypes as an exemplary approach how bioinformatics and particularly machine learning using self organizing maps (SOM) complements modern high-throughput genomic technologies. DNA methylation changes in gliomas comprise both, hyper- and hypomethylation in a subtype specific fashion. We compared pediatric (2 subtypes) and adult (4) glioblastoma and non-neoplastic brain. The functional impact of differential methylation marker sets is discovered in terms of gene set analysis which comprises a large collection of markers related to biological processes, literature data on gliomas and also chromatin states of the healthy brain. DNA methylation signature genes from alternative studies well agree with our signatures. SOM mapping of gene sets robustly identifies similarities between different marker sets even under conditions of noisy compositions. Mapping of previous sets of glioma markers reveals high redundancy and mixtures of subtypes in the reference cohorts. Consideration of the regulatory level of DNA methylation is inevitable for understanding cancer genesis and progression. It provides suited markers for diagnosis of glioma subtypes and disentangles tumor heterogeneity.

Authors: E. Willscher, H. Loffler-Wirth, H. Binder, Lydia Hopp

Date Published: 2015

Publication Type: Not specified

Human Diseases: brain glioma

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