In our research group, we are interested in understanding mechanisms for how protein factors, that interact with chromatin are recruited through DNA –and/or histone binding to change the epigenetic signatures, that affect gene expression.
We study, how such epigentic marks are maintained during DNA replication and cell division to preserve cellular identity and how enviromental influences, such as cellular stress, affects transcriptional programmes and the phenotype of affected cells in human diseases.
Polycomb Group Proteins
Polycomb proteins, first identified as developmental regulators in the fruitfly, Drosophila melanogaster, has been found to be key regulators of timed expression of genes, determining the phenotypic outcome during cellular differentiation of mammalian cells. We are interested in understanding how these polycomb proteins, which can be divided into two major families, the polycomb repressive complex 1 (PRC1) and 2 (PRC2), regulate target genes through histone modifications (methylation and ubiquitination) and cross-talk to chromatin remodelling complexes and DNA methyl transferases. Furthermore, we study if and how signaling pathways downstream of the RAS-ERK and the p38 kinases modulates these polycomb target genes through phosphorylation of histones and the polycomb proteins in response to growth-, differentiation- and stress signals.
Histone Binding Proteins
A histone ”tail” pull down approach has been established to enrich for histone H3 interacting protein complexes, binding to the two repressive marks: H3K9me3 and H3K27me3. Using mass spectrometry, we have been able to identify a number of novel interactors and are currently investigating their importance for transcriptional regulation, using a genomically integrated reporter system. Based on highly specific antibodies, ChIP-on-chip is rutinely used to identify target genes for a number of our novel interactors. Follow up studies are currently being performed to address the importance of those proteins, for the timed regulation of genes required for cell proliferation and differentiation.
The Activity-Dependent Neuroprotective Protein (ADNP)
The Activity-Dependent Neuroprotective Protein (ADNP) which is a vasoactive intestinal peptide (VIP-)-responsive gene during postnatal brain development, was identified as a protein interacting with the H3K9me3 repressive histone mark. The ADNP gene maps to human chromosome 20q12-13.2, a region associated with aggresive tumor growth and found to be amplified in many neoplacias, including bladder-, kidney-, gastric-, ovarian and breast cancer. We have found, that the ADNP protein is required for the proliferation of number of normal and tumor cell lines. We are currently trying to understand how ADNP gets recruited to chromatin, through specific DNA sequences, and likely the H3K9me3 histone mark, and how this might affect gene regulation controlling cell proliferation and differentiation.
Our projects are funded by:
The Lundbeck Foundation, The Novo Nordisk Foundation, The Danish Cancer Society, The Danish Research Council and BRIC.
Gehani S, Agrawal-Singh S, Dietrich N, Christophersen NS, Helin K, Hansen K. Polycomb group protein displacement and gene activation through MSK-dependent H3K27me3S28 phosphorylation. Mol Cell. 2010 Sep 24;39(6):886-900.
Agrawal-Singh S, Koschmieder S, Gelsing S, Stocking C, Stehling M, Thiede C, Thoennissen NH, Köhler G, Valk PJM, Delwel R, Mills K, Bäumer N, Tickenbrock L, Hansen K, Berdel WE, Müller-Tidow C, Serve H (2010). Pim2 cooperates with PML-RAR to induce acute myeloid leukemia in a bone marrow transplantation model. Blood. 2010 Jun 3;115(22):4507-16.
Klaus H. Hansen and Kristian Helin (2009). Epigenetic inheritance through self-recruitment of the Polycomb Repressive Complex 2. Epigenetics 4, 1-6.
Klaus H. Hansen, Adrian Bracken, Diego Pasini, Simmi S. Gehani, Nikolaj Dietrich, Astrid Monrad, Juri Rappsilber, Mads Lerdrup and Kristian Helin (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). Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2. Genes Dev 22, 1345-1355.
Jesper Christensen; Karl Agger; Paul A Cloos; Diego Pasini; Simon Rose; Lau Sennels; Juri Rappsilber; Klaus H Hansen; Anna E Salcini; Kristian Helin (2007). The Retinoblastoma bindning protein 2 belongs to a family of demethylases specific for tri-, and di-methyl lysine 4 on histone H3. Cell 128, 1063-76.
Adrian P. Bracken, Daniela Kleine-Kohlbrecher, Dieogo Pasini, Nikolaj Dietrich, Gaetano Gargiulo, Chantal Beekman, Kim Theilgaard-Mönch, Saverio Minucci, Bo T. Porse, Jean-Christophe Marine, Klaus H. Hansen and Kristian Helin. (2007). The Polycomb group proteins bind througout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 21, 525-530.
Nikolaj Dietrich, Adrian Bracken, Emmanuelle Trinh, Kristian Helin and Klaus H. Hansen (2007). Bypass of senescence by the polycomb protein CBX8 through direct binding to the INK4A-ARF locus. EMBO J. 26(6):1637-48
Cloos PA, Christensen J, Agger K, Maiolica A, Rappsilber J, Antal T, Hansen KH and Helin K. (2006). The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442(7100): 307-11
Adrian Bracken, Nikolaj Dietrich, Diego Pasini, Klaus H. Hansen and Kristian Helin (2006). Genome-wide Mapping of Polycomb Target Genes Unravels their Roles in Cell Fate Transitions. Genes Dev. (9):1123-36.