Identification of transcription factors which are relevant to the progression of IDH-mutant gliomas

• Applicant: Dr. Abigail Kora Suwala
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 532594103

Isocitrate dehydrogenase (IDH)-mutant gliomas are common brain tumors with a dismal prognosis. Many of these tumors present with histological and genetic changes which are linked to poorer outcomes at recurrence (high-grade) that were not present in the initial diagnosis (low-grade). Epigenetic changes are observed during progression, but so far little is known about concrete mechanisms involved. In the proposed research we want to identify specific transcription factors that are relevant to the progression of IDH-mutant gliomas. The first aim is to identify transcription factors that are binding DNA in high-grade but not in low-grade IDH-mutant gliomas (or vice versa) in silico by analyzing DNA methylation, Assay for Transposase-Accessible Chromatin using sequencing (ATAC-Seq), RNA-Seq and liquid chromatography coupled mass spectrometry (LC-MS-MS) proteomic data. As second aim we want to translate the in silico results by verification of transcription factors binding to different extents in low-grade vs high-grade IDH-mutant gliomas using Cleavage Under Targets & Release Using Nuclease (Cut&Run) and/or chromatin immunoprecipitation (ChIP) on patient samples. Knock-downs/-outs in high-grade glioma cell lines followed by proliferation and functional assays will determine the transcription factor’s role in maintaining a high-grade phenotype. As third aim we plan to perform single-cell (sc)ATAC/RNA-Seq on matched low-grade vs high-grade patient samples to elucidate whether epigenetic alterations are transient or stable and how they evolve during tumor progression. In a forth aim we will perform a drug screen in vitro and in vivo to find drugs for future clinical trials that target the specific transcription factors discovered in aim one to three. The proposed work will generate important insight into epigenetic regulation during the progression of IDH-mutant gliomas and identify treatment targets for novel therapeutic approaches.

• DFG Programme: Independent Junior Research Groups