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 epigenetic marks are maintained during DNA replication and cell division to preserve cellular identity and how environmental 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.
Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. Göllner S, Oellerich T, Agrawal-Singh S, Schenk T, Klein HU, Rohde C, Pabst C, Sauer T, Lerdrup M, Tavor S, Stölzel F, Herold S, Ehninger G, Köhler G, Pan KT, Urlaub H, Serve H, Dugas M, Spiekermann K, Vick B, Jeremias I, Berdel WE, Hansen K, Zelent A, Wickenhauser C, Müller LP, Thiede C and Müller-Tidow C.. Nature Medicine, 2017, Jan; 23(1): 69-78.
A High-Density Map for Navigating the Human Polycomb Complexome. Hauri S, Comoglio F, Seimiya M, Gerstung M, Glatter T, Hansen K, Aebersold R, Paro R, Gstaiger M, and Beisel C. Cell Reports., 2016 Oct 4; 17(2): 583-595.
Broad histone H3K4me3 domains in mouse oocytes modulate maternal to zygotic transition. Dahl JA, Jung I, Aanes H, Greggains GD, Manaf A, Lerdrup M, Li G, Kuan S, Li B, Lee AY, Preissl S, Jermstad I, Haugen MH, Suganthan R, Bjørås M, Hansen K, Dalen KT, Fedorcsak P, Ren B and Klungland A.. Nature, Advance online publication (AOP) Sept. 14, 2016 (22 Sept., 2016.)
Differential regulation of the phosphorylation of trimethyl-lysine 27 histone H3 at serine 28 in distinct populations of striatal projection. Bonito-Oliva A, Södersten E, Spigolon G, Hu X, Hellysaz A, Falconi A, Rodrigues-Gomes AL, Broberger C, Hansen K and Fisone G. Neuropharmacology., 2016, August (107), 89-99.
An interactive environment for agile analysis and visualization of ChIP-sequencing data. Lerdrup M, Johansen JV, Agrawal-Singh S and Hansen K. Nature Structural and Molecular Biology., 2016, April 23 (4): 349-57.
A Role for Mitogen- and Stress-Activated Kinase 1 in L-DOPA-induced dyskinesia and DFosB expression. Feyder M, Södersten E, Santini E, Vialou V, LaPlant Q, Watts E, Spigolon G, Hansen K, Caboche J, Nestler E, and Fisone G. Biological Psychiatry., 2016, March 1, 79(5): 362-71.
b-Catenin Regulates Primitive Streak Induction through collaborative Interactions with SMAD2/3 and OCT4. Funa NS, Schachter KA, Lerdrup M, Ekberg J, Hess K, Dietrich N, Honore C, Hansen K and Semb H. Cell Stem Cell., 16, 1-14, June 4, 2015.
Dopamine Signaling leads to loss of Polycomb Repression and Aberrant Gene Activation in Experimental Parkinsonism. Södersten E , Feyder M, Lerdrup M, Gomes AL, Kryh H, Spigolon G, Caboche J, Fisone G and Hansen K. PLoS Genetics., 2014, September 25.
REST-Mediated Recruitment of Polycomb Repressor Complexes in Mammalian Cells. Dietrich N, Lerdrup M, Landt E, Agrawal-Singh S, Bak M, Tommerup N, Rappsilber J, Södersten E and Hansen K. PLoS Genetics., February 2012.
Polycomb group protein displacement and gene activation through MSK-dependent H3K27me3S28 phosphorylation. Gehani S, Agrawal-Singh S, Dietrich N, Christophersen NS, Helin K and Hansen K. Mol Cell., 2010, Sept. 24; 39: 886-900.
A model for transmission of the H3K27me3 epigenetic mark. Hansen K, Bracken A, Pasini D, Gehani SS, Dietrich N, Monrad A, Rappsilber J, Lerdrup M and Helin K. Nat Cell Biol., 2008, Nov;10(11):1291-300.