Cancer Epigenomics
Overview
Epigenetic remodeling in prostate tumors overexpressing BAZ2. Hierarchical clustering identifies two DNA methylation subtypes (from Gu et al., Nat. Genet. 2015)
© NPG
Two general mechanisms have been identified that are involved in the silencing of cancer related genes. Genetic alterations, including mutations and deletions, have been known to be involved in tumor suppression for many years. More recently, DNA methylation has been identified as an additional mechanism to silence genes. Aberrant DNA methylation is an early event in tumorigenesis and a major contributor in the development of solid tumors as well as leukemias. As an epigenetic alteration, DNA methylation does not change the sequence of a gene and thus offers the exciting possibility for therapeutic removal of the methylation group by demethylating drugs.
We are investigating aberrant DNA methylation events in human malignancies with a focus on acute myeloid leukemia, chronic lymphocytic leukemia, lung cancer and prostate cancer.
Recent findings include the identification of non-random and tumor-type specific methylation changes in human malignancies, the identification of novel cancer related genes preferentially silenced in these malignancies by epigenetic mechanisms and the development of strategies for the identification of epigenetic markers for diagnosis and those with prognostic value.
With these approaches it should be possible to understand regulation of normal DNA methylation events and to apply this knowledge to better understand the deregulations seen in human cancer.
Major research directions
- Genome–wide scans for DNA methylation in human and mouse malignancies using state-of-the-art profiling protocols e.g. next generation sequencing or methylation arrays
- Cancer gene identification and functional characterization
- Mechanisms of epigenetic gene silencing
- Non-genetic mechanisms of therapy resistance
Selected publications
- Costello JF, Frühwald MC, Smiraglia DJ, ... Plass C. Aberrant CpG island methylation has non-random and tumor type specific patterns. Nature Genetics, 25:132-138, 2000.
- Yu L, Liu C, Vandeusen J, ... Plass C. Global assessment of promoter methylation in a murine model of cancer identifies ID4 as a putative novel tumor suppressor gene in human leukemia. Nature Genetics, 37:265-274, 2005.
- Raval A, Tanner S, Byrd J,... Plass C. Down-regulation of death associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 129:879-890, 2007.
- Schwartzentruber J, Korshunov A, Liu XY, ... Plass C, Majewski J, Pfister SM, Jabado N.Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature, 482(7384): 226-31, 2012.
- Sturm D, Witt H, Hovestadt V, ... Lichter P, Plass C, Jabado N, Pfister SM. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell, 22(4): 425-37, 2012.
- Tönjes M, Barbus S, Park YJ, ... Plass C, Okun JG, Reifenberger G, Lichter P, Radlwimmer B. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med., 19(7): 901-8, 2013.
- Wang Q, Gu L, Adey A, Radlwimmer B, Wang W, Hovestadt V, Bähr M, Wolf S, Shendure J, Eils R, Plass C, Weichenhan D. Tagmentation-based whole-genome bisulfite sequencing. Nat Protoc. 8: 2022-32, 2013.
- Jäger N, Schlesner M, Jones DT, .... Plass C, Siebert R, Trumpp A, Rippe K, Lehmann I, Lichter P, Pfister SM, Eils R. Hypermutation of the inactive x chromosome is a frequent event in cancer. Cell 155: 567-81, 2013.
- Bender S, Tang Y, Lindroth AM, ...Plass C, Cho YJ, Pfister SM. Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas. Cancer Cell, 24: 660-72, 2013.
- Plass C, Pfister SM, Lindroth AM, Bogatyrova O, Claus R, Lichter P. Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nat Rev Genet. 14: 765-80, 2013.
- Oakes CC, Claus R, Gu L, Assenov Y, ... Plass C. Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia. Cancer Discov. 2014, 4: 348-61, 2014.
- Cabezas-Wallscheid N, Klimmeck D, Hansson J, Lipka DB, ... Milsom MD, Plass C, Krijgsveld J, Trumpp A. Identification of Regulatory Networks in HSCs and Their Immediate Progeny via Integrated Proteome, Transcriptome, and DNA Methylome Analysis.Cell Stem Cell 15: 507-22, 2014.
-
Gu L, Frommel SC, Oakes CC, Simon R, ... Schlomm T, Sauter G, Eils R, Plass C, Santoro R. BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence. Nat Genet 47: 22-30, 2015.
- Oakes CC, Seifert M, Assenov Y, Gu L, ... Plass C. Progressive epigenetic programming during B cell maturation yields a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat Genet 48: 253-64, 2016.
- Brocks D, Schmidt CR, Daskalakis M, ... Plass C. DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats. Nat Genet 49: 1052-1060, 2017.
- Gerhauser C, Favero F, Risch T, Simon R, Feuerbach L, Assenov L, ... Brors B, Sauter G, Plass C, Yaspo ML, Korbel JO, Schlomm T, Weischenfeldt J. Molecular evolution of early onset prostate cancer identifies novel molecular risk markers and clinical trajectories. Cancer Cell 2018, 34(6): 996-1011, 2018.
- Wierzbinska JA, Toth R, Ishaque N, Rippe K, Mallm JP, Klett LC, Mertens D, Zenz T, Hielscher T, Seifert M, Küppers R, Assenov Y, Lutsik P, Stilgenbauer S, Roessner PM, Seiffert M, Byrd J, Oakes CC, Plass C, Lipka DB. Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL. Genome Med. 12: 29, 2020.
- Bakr A, Hey J, Sigismondo G, Liu CS, Sadik A, Goyal A, Cross A, Iyer RL, Müller P, Trauernicht M, Breuer K, Lutsik P, Opitz CA, Krijgsveld J, Weichenhan D, Plass C, Popanda O, Schmezer P. ID3 promotes homologous recombination via non-transcriptional and transcriptional mechanisms and its loss confers sensitivity to PARP inhibition. Nucleic Acids Res. 49, 11666-11689, 2021.
- Hey J, Paulsen M, Toth R, Weichenhan D, Butz S, Schatterny J, Liebers, Lutsik P, Plass C & Mall MA. Epigenetic reprogramming of airway macrophages drives polarization and inflammation in muco-obstructive lung disease. Nat Commun. 12: 6520, 2021.