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How glioma develops

Scientists from the PAS Institute of Computer Science, the Nencki Institute and the University of Warsaw created the first "Atlas" of regulatory areas active in gliomas of various degrees of malignancy. The study provides a better understanding of the mechanisms of glioblastoma development. The research results have been recently published in the Nature Communications.

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Freshly resected glioma specimens were acquired from patients representing major glioma malignancy groups: pilocytic astrocytomas, diffuse astrocytomas and glioblastomas. Clinical data about each patient was collected. Glioma tissues were homogenized to a single cell suspension and experimentally defined cell numbers of cells were split into portions that were processed for RNA-seq, ATAC-seq, ChIP-seq, or DNA methylation experiments. Differential analysis of epigenomic and transciptomic profiles across glioma grades was performed, followed by identification of related regulatory mechanisms. Results from all genome-wide experiments were made available in a genome browser. Source: PAS Institute of Computer Science.

Gliomas are brain tumors, in which the proper regulation of gene expression is frequently impaired, resulting in uncontrolled tumor growth and impairment of brain functions. Malignant, hard-to-treat gliomas are more prevalent in older adults, while low-grade gliomas which give a greater chance of recovery occur more commonly in children.

The group of researchers working on the atlas conducted a comprehensive, whole-genome analysis of epigenetic patterns in over 30 samples of benign and malignant tumors collected at clinical centers in Warsaw. For the first time, scientists investigated simultaneously the profiles of open chromatin, histone modifications, DNA methylation and gene expression in tissues of patients using freshly resected gliomas. All molecular clues were used to identify regulatory elements, such as promoters that control the expression of adjacent genes, and enhancers that direct the expression of distant genes.

New mechanisms

Scientists have identified the mechanisms regulating gene expression in low- and high-grade gliomas. They predicted a new pathway for regulating gene expression related to glioma malignancy of gliomas and confirmed that this pathway controls cell migration and invasiveness of glioblastoma cells. Their atlas of active regulatory regions in gliomas of various degrees of malignancy and in the brain is available online.

“Our findings have led to the construction of the first comprehensive atlas of active regulatory elements in gliomas, which enabled the identification of functional regions such as enhancers and promoters in patient samples. This comprehensive approach revealed epigenetic patterns influencing gene expression in benign gliomas, and a novel tumor-related mechanism involving the FOXM1-driven signaling pathway controlling glioblastoma cell invasion and migration. Atlas provides a gigantic dataset that can be used for further analyses and comparisons with existing and new datasets. This will inspire new discoveries, and allow better understanding of glioblastoma development”, says Dr. Karolina Stępniak and Dr. Jakub Mieczkowski, the first authors of the publication. The provided atlas containing a huge dataset will help understand the importance of the non-coding regions of the genome that are active in the brain and the key mechanisms for glioblastoma development and make new discoveries.

The interdisciplinary project has been carried out by the teams of Prof. Bożena Kamińska (Nencki Institute of Experimental Biology, Polish Academy of Sciences), Assoc. Prof. Bartosz Wilczyński (Institute of Informatics, University of Warsaw) and Dr. Michał J. Dąbrowski (Institute of Computer Science, Polish Academy of Sciences). Project entitled "Atlas of regulatory areas specific for the human brain – a new tool for discovering the pathways causing selected brain diseases" was financed by the National Science Center under Symphony 3 grant.

The article "Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas" has been recently published in Nature Communications.

Source of information: PAS Institute of Computer Science