PhD position bioinformatics (m/f/d)

PhD position bioinformatics (m/f/d)
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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.

In this project we aim to analyze the occurrence of alternative promoter usage in brain cancer on transcriptomic level using short-read and long-read (Oxford nanopore) RNA sequencing data. This offers the opportunity to discover larger alternative transcripts and potential candidates for targeted treatments, which are likely to be missed with the standard short-read sequencing protocol. The material and most of the data are already available at our institute, so you can start with the analyses straight away. Furthermore, we want to validate alternative transcripts on the protein level (in the same patient cohort) using mass-spectrometry data that is currently being generated. We will build upon an existing framework for covariation analysis (Bludau et al. 2021) to integrate the RNA and protein expression profiles. This multi-omics approach offers a unique opportunity to identify clinically relevant alternative promoter usage in IDH-mutant gliomas. The computational workflow developed in this project should further be generalized for applications to other tumor types where alternative promotor usage might be relevant, thus offering a broad clinical impact.

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 MY, Hong C, Doudna JA, Chang SM, Phillips JJ, Solomon DA, Costello JF. Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer. Nat Commun. 2022 Sep 16;13(1):5430. doi: 10.1038/s41467-022-33099-x. PMID: 36114166; PMCID: PMC9481613.

Suwala AK, Stichel D, Schrimpf D, Maas SLN, Sill M, Dohmen H, Banan R, Reinhardt A, Sievers P, Hinz F, Blattner-Johnson M, Hartmann C, Schweizer L, Boldt HB, Kristensen BW, Schittenhelm J, Wood MD, Chotard G, Bjergvig R, Das A, Tabori U, Hasselblatt M, Korshunov A, Abdullaev Z, Quezado M, Aldape K, Harter PN, Snuderl M, Hench J, Frank S, Acker T, Brandner S, Winkler F, Wesseling P, Pfister SM, Reuss DE, Wick W, von Deimling A, Jones DTW, Sahm F. Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1. Acta Neuropathol. 2021 Jul;142(1):179-189. doi: 10.1007/s00401-021-02302-6. Epub 2021 Apr 19. PMID: 33876327; PMCID: PMC8217054.

Suwala AK, Felix M, Friedel D, Stichel D, Schrimpf D, Hinz F, Hewer E, Schweizer L, Dohmen H, Pohl U, Staszewski O, Korshunov A, Stein M, Wongsurawat T, Cheunsuacchon P, Sathornsumetee S, Koelsche C, Turner C, Le Rhun E, Mühlebner A, Schucht P, Özduman K, Ono T, Shimizu H, Prinz M, Acker T, Herold-Mende C, Kessler T, Wick W, Capper D, Wesseling P, Sahm F, von Deimling A, Hartmann C, Reuss DE. Oligosarcomas, IDH-mutant are distinct and aggressive. Acta Neuropathol. 2022 Feb;143(2):263-281. doi: 10.1007/s00401-021-02395-z. Epub 2021 Dec 30. PMID: 34967922; PMCID: PMC8742817.

Bludau, I., Frank, M., Dörig, C. et al. Systematic detection of functional proteoform groups from bottom-up proteomic datasets. Nat Commun 12, 3810 (2021). https://doi.org/10.1038/s41467-021-24030-x

• Job-ID: V000012628
• Field of application: Neuropathologie
• Location: Heidelberg
• Start date: as of now
• Job Category: Science and teaching
• Working hours: Part time (65%)
• Published: 05.04.2024
• Limitation:Temporary (31.10.2027, extension ist sought)
• Contract:TV-L

Tasks

• Analyses of RNA long-read and short-read sequencing
• Analyses of mass-spectrometry data

Profile

• Bioinformatics background (using R, Python)
• Interest in the project

What we offer

• Goal-oriented, individual training and development opportunities Klicken Sie hier, um Text einzugeben.
• Working with the latest techniques / technical equipment Klicken Sie hier, um Text einzugeben.
• Possibility of mobile working
• Flexible working hours within the framework of flexitime
• Possibility of doctorate
• Possibility to publish scientifically is offered and supported
• Regular team meetings
• Collectively agreed remuneration, attractive company pension scheme (VBL)
• 30 days vacation
• Sustainable travel: job ticket
• Family-friendly working environment: cooperative arrangements for childcare, subsidy for child vacation care, advice for employees with relatives in need of care
• Wide range of health, prevention and sports offers

Contact & Application

For further information please contact Abigail Suwala  via e-mail.

Interested?

Applications will be accepted until 12.05.2024  via e-mail.

Neuropathologie
Abigail Suwala, MD
Im Neuenheimer Feld 224
69120 Heidelberg
[email protected]

Note: The UKHD is subject to the provisions of the Infektionsschutzgesetz. Therefore, a valid measles immunity certificate is required for all persons employed at the UKHD.

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