The major aim of the work in our research group is to understand the molecular mechanisms leading to cancer.
Cancer is a genetic disease, which develops as a consequence of a number of activating and inactivating mutations in our genes. These mutations affect the cellular growth and the destiny of our normal cells, and cancer is believed to develop from normal cells during differentiation.
To achieve our aim, we investigate the mechanisms that regulate cell-fate decisions in stem cells, differentiated cells as well as tumor cells. Our main focus areas and experimental approaches include:
1. Global functional, genomic and proteomic approaches to identify and characterize novel genes and mechanisms involved in the development of human cancer.
Identification and characterization of novel players regulating the orderly progression through the mammalian cell cycle, including those involved in regulating tumor suppressor mechanisms such as senescence and apoptosis.
Identification and characterization of genes involved in cell-fate decisions of embryonic and adult stem cells.
2. Targeted approaches to understand the function of cancer relevant gene families with a particular focus on epigenetic regulators, such as histone methyltransferases, lysine demethylases and Polycomb Group proteins.
Identification and characterization of up- and downstream regulators using proteomics and genomic approaches.
Elucidation of biochemical and biological function of histone methyltransfeases, lysine demethylases and Polycomb Group proteins.
3. Development of mouse models for understanding protein function and cancer development.
4. Development and characterization of small molecule inhibitors for the treatment of cancer.
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.
Article from Politiken 15 May, 2015 by Henrik Larsen (in Danish)
"Genetisk fejl spiller central rolle ved blodkræft"
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.
Wu X, Johansen JV and Helin K (2013). Fbxl10/Kdm2 recruits Polycomb Repressive Complex 1 to CpG-islands and regulates H2A ubiquitylation. Mol Cell, 49, 1134–1146.
Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PA, Rappsilber J,
Helin K. TET1 and hydroxymethylcytosine in transcription and DNA methylation
fidelity. Nature, 473, 343-8.
Kleine-Kohlbrecher D, Christensen J, Vandamme J, Abarrategui I, Bak M, Tommerup N, Shi X, Gozani O, Rappsilber J, Salcini AE, Helin K (2010). A Functional Link between the Histone Demethylase PHF8 and the Transcription Factor ZNF711 in X-Linked Mental Retardation. Mol Cell 38, 165-178.
Pasini D, Cloos PA, Walfridsson J, Olsson L, Bukowski JP, Johansen JV, Bak M,
Tommerup N, Rappsilber J, Helin K (2010). JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature 464, 306-310.
Melixetian M, Klein DK, Sørensen CS and Helin K (2009). NEK11 regulates CDC25A degradation and the IR-induced G2/M checkpoint. Nature Cell Biology 11, 1247-1253.
Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J and Helin K (2009). The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev 23, 1171-1176.
Hansen KH, Adrian Bracken A, Pasini D, Gehani SS, Dietrich N, Monrad A, Rappsilber J, Lerdrup M and Helin K (2008). A model for transmission of the H3K27me3 epigenetic mark. Nature Cell Biology 10, 1291-1300.
Pasini D, Hansen KH, Christensen J, Agger K, Cloos PA and Helin K (2008). Functional interaction between the RBP2 H3K4 demethylase and the Polycomb Repressive Complex 2. Genes Dev 22, 1345-1355.
Agger K, Christensen J, Cloos PA, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE and Helin K (2007) UTX and JMJD3 are H3K27 demethylases involved in HOX gene regulation and development. Nature 449, 731-734.
Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Mönch K, Minucci S, Porse BT, Marine JC, Hansen KH and Helin K (2007). The Polycomb group proteins bind throughout the INK4A-ARF locus and are dissociated in senescent cells. Genes Dev 21, 525-530.
Christensen J, Agger K, Cloos P, Pasini D, Rose S, Sennels L, Rappsilber J, Hansen KH, Salcini AE and Helin K (2007) RBP2 belongs to a family of demethylases specific for tri- and di-methylated lysine 4 on Histone 3. Cell, 128, 1063-1076.
Bracken AP, Dietrich N, Pasini D, Hansen KH and Helin K (2006). Genome-wide mapping of Polycomb target genes unravels their role in cell-fate transitions. Genes Dev 20, 1123-1136.
Cloos PAC, Christensen J, Agger K, Maiolica A, Rappsibler J, Antal T, Hansen KH and Helin K (2006) The putative oncogene GASC1/JMJD2c demethylates tri- and di-methylated lysine 9 on histone H3, Nature 442, 307-311.
Selected recent reviews
Laugesen A and Helin K (2014). Chromatin Repressive Complexes in Stem Cells, Development and Cancer. Cell Stem Cell 14, 735-751.
Di Croce L and Helin K (2013). Transcriptional regulation by Polycomb group proteins. Nature Struct Mol Biol 20, 1147-1155.
Helin K and Dhanak D (2013) Chromatin proteins and modifications as drug targets. Nature, 502, 480-488.
Højfeldt JW, Agger K, and Helin K (2013). Histone Lysine Demethylases as Targets for Anti-Cancer Therapy. Nature Rev Drug Discov, 12, 917-930.
Kooistra SM and Helin K (2012). Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol, 13, 297-311.