The main goal of our research is to contribute to the understanding of the molecular mechanisms leading to cancer and to identify proteins that are required for cancer maintenance as potential new targets for therapy.
Our aim is to make contributions towards eradicating cancer. To achieve this, we believe it is essential to understand the mechanisms leading to the development of cancer and to identify the vulnerabilities of cancer cells. Our approach is to study how cell-fate decisions are regulated, and how these become perturbed in cancer. Moreover, we are using cancer models to identify potential novel therapeutic targets for anti-cancer therapy.
Polycomb Group Proteins
- Demonstration that H3 lysine 27 tri-methylation (H3K27me3) and the Polycomb group proteins provide a blueprint for transcriptional repression of genes governing cell-fate decisions (Bracken et al, 2006, Genes Dev).
- Molecular and mechanistic insights into how Polycomb group proteins regulate gene expression and cell-fate decisions (Hansen et al, 2008, Nat Cell Biol; Pasini et al, 2010, Nature; Wu et al, 2013, Mol Cell; Riising et al, 2014, Mol Cell; Højfeldt et al, 2019, Mol Cell).
- Discovered that the Polycomb group protein EZH2 is overexpressed in cancer and is a potential therapeutic target in childhood brain cancer (Bracken et al, 2003, EMBO J; Mohammad et al, 2017, Nat Med).
A New Class of Epigenetic Enzymes
- Discovery of enzymes that demethylates H3K9me3/me2 and H3K36me3/me2 (Cloos et al, 2006, Nature), H3K27me3/me2 (Agger et al, 2007, Nature), H3K4me3/me2 (Christensen et al, 2007, Cell) and H3K9me2/me1 (Kleine-Kohlbrecher et al, 2010, Mol Cell).
- Demonstration of the essential role of lysine demehtylation in regulating cellular senescence (Agger et al, 2009 Genes Dev), neuronal differentiation (Schmitz et al, 2011, EMBO J; Albert et al, 2013, PLoS Genet), ES cell self-renewal and early development (Pedersen et al, 2016, EMBO J) and the maternal-to-zygotic transition (Sankar et al, 2020 Nat Cell Biol)
- Discovery of role for the lysine demethylases in the development and maintenance of cancer (Cloos et al, 2006, Nature; Sroczynska et al, 2014, Blood; Agger et al, 2016, Genes Dev)
- Establishment of biotech company, EpiTherapeutics, developing small molecule inhibitors for the targeting of lysine demethylases in cancer (Heinemann et al, 2014, Nature)
DNA Methylation and Cancer
- Demonstration of a role for the TET1 hydroxy-methyl transferase in regulating transcription and DNA methylation fidelity (Williams et al, 2011, Nature).
- Demonstration that loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis (Rasmussen et al, 2015, Genes Dev).
- Determination of the mechanism by which TET2 regulate transcription and how its loss contribute to blood cancer (Rasmussen et al, 2019, Genome Res).
The pRB-E2F Pathway
- Identification and cloning of the transcription factor E2F1, a target for the tumor suppressor protein, pRB (Helin et al, 1992, Cell).
- Demonstration that the E2F transcription factors consist of a large family of proteins and that they heterodimerize with DP factors (Helin et al, 1993, Genes Dev; Lees et al, 1993, Mol Cell Biol; Helin et al, 1993, Mol Cell Biol; Cartwright et al, 1998, Oncogene, DiStefano et al, 2003, EMBO J; Christensen et al, 2005, Nucl Acids Res).
- Demonstration that the E2F transcription factors directly regulate genes involved in differentiation, development, proliferation and apoptosis (Müller et al, 2001, Genes Dev; Moroni et al, 2001, Nat Cell Biol; Bracken et al, 2003, EMBO J)
- Demonstration of an intricate crosstalk between the pRB- and p53-pathways regulating a G1-checkpoint and entry into S phase (Lomazzi et al, 2002, Nat Genet).
DNA Replication and Cell Cycle Control
- Demonstration of mechanisms for how origins of DNA replication are restricted to fire only once per cell cycle (Petersen et al, 1999, EMBO J; Petersen et al, 2000, Genes Dev; Melixetian et al, 2014 J Cell Biol; Ballabeni et al, 2004, EMBO J).
- Demonstration of a role for the NEK11 kinase in regulating the IR-induced G2/M checkpoint (Melixetian et al, 2009, Nat Cell Biol).
We are working on two major lines of research. In one line we are focusing on hypothesis-driven projects to understand the molecular mechanisms by which specific proteins regulate gene expression and cell-fate decisions. Most of the proteins we working on are chromatin-associated proteins and some of these have epigenetic function. The second line of research is more discovery oriented. Here, we are using CRISPR-Cas9 based approaches to identify genes regulating cellular processes, such as ES self-renewal and differentiation, or being required for the proliferation of glioblastoma or acute myeloid leukemia.
- Højfeldt JW, Hedehus L, Laugesen A, Tatar T, Wiehle L, and Helin K (2019). Non-core subunits of the PRC2 complex are collectively required for its target specificity. Mol Cell 76, 423-436.
- Radzisheuskaya A, Shliaha P, Grinev V, Lorenzini E, Kovalchuk S, Shlyueva D, Gorshov V, Jensen ON and Helin K (2019). PRMT5 methylome profiling uncovers a direct link to splicing regulation in human acute myeloid leukemia. Nat Struct Mol Biol 26, 999-1012.
- Mohammad F, Weissmann S, Leblanc B, Pandey DP, Højfeldt JW, Comet I, Zheng C, Johansen JV, Rapin N, Porse BT, Tvardovskiy A, Jensen ON, Olaciregui NG, Lavarino C, Suñol M, de Torres C, Mora J, Carcaboso AM and Helin K (2017). EZH2 is a potential therapeutic target for H3K27M mutant pediatric gliomas. Nature Medicine 23, 483-492.
- Agger K, Miyagi S, Pedersen MT, Kooistra SM, Johansen JV and Helin K (2016). Jmjd2/Kdm4 demethylases are required for expression of interleukin 3 receptor alpha and survival of acute myeloid leukemia cells. Genes Dev 30, 1278-1288.
- Rasmussen KD, Jia G, Johansen JV, Pedersen MT, Rapin N, Bagger FO, Porse BT, Bernard OA, Christensen J and Helin K (2015). Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis. Genes Dev, 29, 910-922.
- Riising EM, Comet I, Leblanc B, Wu X, Johansen JV and Helin K (2014). Gene Silencing Triggers Polycomb Repressive Complex 2 recruitment to CpG islands genome wide. Mol Cell 55, 347-360.
In the media
Article from BioZoom, June 2018 by Helene Halkjær Jensen (in Danish).
Host: Peter Lund Madsen (in Danish) 23 July 2018.
YouTube video 13 December 2017.
Article from Politiken 15 May, 2015 by Henrik Larsen (in Danish).
Podcast Carlsbergfondet 22 April 2017.
Program for translational hematology (PTH)
PTH is a translational research program aiming at improving immediate and long-term clinical outcome for hematological patients. Through interdisciplinary basic and clinical research, we work together to uncover mechanisms leading to hematopoietic malignancies, identify new potential drug targets, and to improve the treatments for these malignancies.