Posttranslational modifications of histone proteins in human brain tumors

• Applicant: Professor Dr. Andreas von Deimling
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Developmental Biology ; Pathology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505276113

Nuclear DNA is wrapped around histone complexes for most of the time during the cell cycle. These octameric complexes consist of two each of the histone proteins H2A, H2B, H3 and H4. DNA replication or transcription requires the separation of DNA from the histone complex. Their affinity to the complex is strongly modulated by modifications of the histone proteins. The modifications are mediated enzymatically and consist of methylation, phosphorylation, acetylation and other modifications. Depending on the extent and pattern of the modifications, the DNA is maximally condensed or loosened and thus accessible for transcription. Thus, gene regulation is decisively influenced by the pattern of histone modifications. Histone-mediated gene regulation is assigned to the field of epigenetics. Therefore, in each cell a tissue- and development-specific pattern of histone protein modifications, a so-called histone code, can be assumed. Our own preliminary investigations have shown that two specific brain tumors, astrocytomas and oligodendrogliomas, differ clearly and reproducibly in the pattern of their histone code. Histone modifications are already used as a starting point for tumor therapies. This is especially true for inhibitors of histone deacetylases, because deacetylated histones bind DNA more tightly and thus inhibit DNA transcription, which is particularly active in tumors. Other modifications are also currently seen as possible therapeutic targets in tumor therapy. This project aims to systematically determine the histone code from the entire spectrum of human brain tumors. For this purpose, surgically removed tumor tissue will be analyzed by mass spectrometry. An entity specific pattern is expected, which will be investigated in different directions: Does knowledge of the histon code allow insights to mechanisms essential for tumor initiation and progression? Is the histone code sufficiently tumor type specific that the categorization and evaluation of brain tumors can be expanded and sharpened? The answer to this question requires a comparison with histological and molecular data. Here, another dimension of epigenetics, plays an important role, namely the methylation analysis of brain tumors. In recent years, methylation analysis has developed into an extremely powerful tool for the classification of brain tumors. Grouping according to methylation-based tumor classification will be basis for this program. Can relevant information for targeted therapy be extracted from the histone code? For this purpose, extensive analyses of the interaction of the respective modifications with tumor-relevant cellular pathways will be carried out. In summary, a new approach for analysis of human brain tumors will be developed and implemented. The data from these analyses will provide insights into tumor formation, will be basis for a new approach to classification and will provide targets for development of novel therapies.

• DFG Programme: Reinhart Koselleck Projects