Phd Position Bioinformatics
vor 4 Wochen
searched at the **Neuropathology department**.
**Project describtion: Alternative promoter usage in brain cancer**
DNA methylation has a major impact on gene regulation. Reduced DNA methylation can change access to promoter regions and increase the usage of alternative (non-canonical) promoters, a process that is elevated in cancer cells (Hon et al., 2012, Esteller et al., 2007). Alternative promoter usage in cancer can lead to the formation of tumor specific antigens, which can furthermore be used as therapeutic targets (Shah et al., 2023, Wiesner et al., 2015).
Little is known about the usage of alternative promoters in brain cancer. Our institute has extensive experience with using DNA methylation for brain tumor diagnostics (Capper et al., 2018) and functional epigenetics (Barger*, **Suwala** et al., 2022). Certain entities, like IDH-mutant gliomas, show shifts in their methylation profile during progression (**Suwala** et al., 2021 and 2022), indicating that alternative promoter events could play a role in the malignancy process of these tumors.
The ultimate goal is to identify novel therapies that can significantly improve patient outcomes. Working closely with the teams of the Clinical Cooperation Unit Neuropathology at DKFZ and the diagnostic Department of Neuropathology will ensure that our findings are rapidly translated into clinical practice.
References:
Hon GC, Hawkins RD, Caballero OL, Lo C, Lister R, Pelizzola M, Valsesia A, Ye Z, Kuan S, Edsall LE, Camargo AA, Stevenson BJ, Ecker JR, Bafna V, Strausberg RL, Simpson AJ, Ren B. Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res. 2012 Feb;22(2):246-58. doi: 10.1101/gr.125872.111. Epub 2011 Dec 7. PMID: 22156296; PMCID: PMC3266032.
Esteller M. Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet. 2007 Apr 15;16 Spec No 1:R50-9. doi: 10.1093/hmg/ddm018. PMID: 17613547.
Shah NM, Jang HJ, Liang Y, Maeng JH, Tzeng SC, Wu A, Basri NL, Qu X, Fan C, Li A, Katz B, Li D, Xing X, Evans BS, Wang T. Pan-cancer analysis identifies tumor-specific antigens derived from transposable elements. Nat Genet. 2023 Apr;55(4):631-639. doi: 10.1038/s41588-023-01349-3. Epub 2023 Mar 27. PMID: 36973455.
Wiesner T, Lee W, Obenauf AC, Ran L, Murali R, Zhang QF, Wong EW, Hu W, Scott SN, Shah RH, Landa I, Button J, Lailler N, Sboner A, Gao D, Murphy DA, Cao Z, Shukla S, Hollmann TJ, Wang L, Borsu L, Merghoub T, Schwartz GK, Postow MA, Ariyan CE, Fagin JA, Zheng D, Ladanyi M, Busam KJ, Berger MF, Chen Y, Chi P. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature. 2015 Oct 15;526(7573):453-7. doi: 10.1038/nature15258. Epub 2015 Oct 7. PMID: 26444240; PMCID: PMC4807020.
Demircioğlu D, Cukuroglu E, Kindermans M, Nandi T, Calabrese C, Fonseca NA, Kahles A, Lehmann KV, Stegle O, Brazma A, Brooks AN, Rätsch G, Tan P, Göke J. A Pan-cancer Transcriptome Analysis Reveals Pervasive Regulation through Alternative Promoters. Cell. 2019 Sep 5;178(6):1465-1477.e17. doi: 10.1016/j.cell.2019.08.018. PMID: 31491388.
Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, Koelsche C, Sahm F, Chavez L, Reuss DE, Kratz A, Wefers AK, Huang K, Pajtler KW, Schweizer L, Stichel D, Olar A, Engel NW, Lindenberg K, Harter PN, Braczynski AK, Plate KH, Dohmen H, Garvalov BK, Coras R, Hölsken A, Hewer E, Bewerunge-Hudler M, Schick M, Fischer R, Beschorner R, Schittenhelm J, Staszewski O, Wani K, Varlet P, Pages M, Temming P, Lohmann D, Selt F, Witt H, Milde T, Witt O, Aronica E, Giangaspero F, Rushing E, Scheurlen W, Geisenberger C, Rodriguez FJ, Becker A, Preusser M, Haberler C, Bjerkvig R, Cryan J, Farrell M, Deckert M, Hench J, Frank S, Serrano J, Kannan K, Tsirigos A, Brück W, Hofer S, Brehmer S, Seiz-Rosenhagen M, Hänggi D, Hans V, Rozsnoki S, Hansford JR, Kohlhof P, Kristensen BW, Lechner M, Lopes B, Mawrin C, Ketter R, Kulozik A, Khatib Z, Heppner F, Koch A, Jouvet A, Keohane C, Mühleisen H, Mueller W, Pohl U, Prinz M, Benner A, Zapatka M, Gottardo NG, Driever PH, Kramm CM, Müller HL, Rutkowski S, von Hoff K, Frühwald MC, Gnekow A, Fleischhack G, Tippelt S, Calaminus G, Monoranu CM, Perry A, Jones C, Jacques TS, Radlwimmer B, Gessi M, Pietsch T, Schramm J, Schackert G, Westphal M, Reifenberger G, Wesseling P, Weller M, Collins VP, Blümcke I, Bendszus M, Debus J, Huang A, Jabado N, Northcott PA, Paulus W, Gajjar A, Robinson GW, Taylor MD, Jaunmuktane Z, Ryzhova M, Platten M, Unterberg A, Wick W, Karajannis MA, Mittelbronn M, Acker T, Hartmann C, Aldape K, Schüller U, Buslei R, Lichter P, Kool M, Herold-Mende C, Ellison DW, Hasselblatt M, Snuderl M, Brandner S, Korshunov A, von Deimling A, Pfister SM. DNA methylation-based classification of central nervous system tumours. Nature. 2018 Mar 22;555(7697):469-474. doi: 10.1038/nature26000. Epub 2018 Mar 14. PMID: 29539639; PMCID: PMC6093218.
Barger CJ, Suwala AK, Soczek KM, Wang AS, Kim M
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