Specialist from IRA 3P Medicine Laboratory is co-author of the publication about glioma

5.07.2021

Dr. Habil. Jakub Mieczkowski

Dr. Habil. Jakub Mieczkowski from the International Research Agenda 3P Medicine Laboratory at the Medical University of Gdańsk is one of the research team members responsible for the computational part of the project Atlas of regulatory areas specific for the human brain – a new tool for discovering the pathways causing selected brain diseases. Project has been developed by scientist from the Nencki Institute of the Polish Academy of Sciences, University of Warsaw and Institute of Computer Science of the PAS. Results of the research have been published in the Nature Communications on 15th of June 2021, revealing deregulation of mechanisms controlling gene expression and a new mechanism driving the invasion of malignant brain tumors.

The interdisciplinary project Symphony 3 entitled Atlas of regulatory areas specific for the human brain – a new tool for discovering the pathways causing selected brain diseases, financed by the National Research Center NCN, has been carried out by the teams of Prof. Bożena Kamińska from the Nencki Institute of Experimental Biology of the AS, Dr. Habil. Bartosz Wilczyński from the Faculty of Mathematics, Informatics and Mechanics, UW and Dr. Michał J Dąbrowski from the Institute of Computer Science of the PAS.

The most important findings:

• Revealing the mechanisms regulating gene expression in benign and malignant gliomas,
• predicting a new pathway for regulating gene expression related to glioma malignancy and confirming that this pathway controls cell migration and invasiveness in glioblastoma cells,
• Creating and sharing an Atlas of active regulatory regions in gliomas of various degrees of malignancy and in the brain.

- The human genome is a vast set of instructions that are read and interpreted to produce cellular proteins and enable proper functions of cells and tissues. Less than 2% of the human DNA encodes proteins, therefore decoding the functions of the remaining non-coding regions is a great challenge – says Dr. Habil. Jakub Mieczkowski. – There are tens of thousands of genes active in each tissue, and understanding how they are regulated would allow us to better understand the functions of the cell. In a cell, a strand of DNA is wrapped around proteins called histones and forms a highly organized structure called chromatin. Biochemical changes in histones contribute to the openness or lack of access to chromatin, and can stimulate or inhibit gene expression (these processes are called epigenetics). Enzymes can access and read instructions contained in DNA only at the open chromatin sites. Genome-wide mapping of regulatory regions and open chromatin provides a glimpse how genes are regulated in specific cells and under physiological or pathological conditions. Changes in the chromatin openness are regulated by epigenetic processes that ensure their endurance, influence the reading of specific genes and, in the result drive cellular processes. Deregulation of gene expression often occur during the tumor development. The processes regulating chromatin openness are reversible and can be adjusted externally, therefore controlling chromatin openness has a high clinical potential.

Screenshot from the Atlas…

- 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 gliomas are most common in the elderly, are resistant to standard therapy and have a very poor prognosis. Benign gliomas occur mainly in children and have a better prognosis, but if left untreated, they can develop into malignant tumors – explains Dr. Habil. Jakub Mieczkowski.

In collaboration with neurosurgeons from Warsaw hospitals, a unique collection of tumor samples was collected and a comprehensive, whole-genome analysis of epigenetic patterns in samples of benign and malignant tumors was performed. The comparison of the patterns revealed specific processes related to malignant tumorigenesis. For the first time, researchers investigated simultaneously the patterns of chromatin openness, histone changes, DNA methylation and gene expression in more than 30 brain tumor samples. 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.

The scientists’ Atlas…, provides a better understanding of the importance of the non-coding regions of the genome that are active in the human brain. Moreover, findings revealed new mechanisms that control tumorigenesis in brain tumors.

- Our findings 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 – say the first authors of the publication: Karolina Stępniak Ph.D. and Dr. Habil. Jakub Mieczkowski, who has also told about the project in the Polish-language interview with Prof. Bożena Kamińska: