Epigenetics and Cellular Biology

Group Site: 
Group Leader: 

Susanne Müller-Knapp

Group Info

Research Areas

Epigenetics refers to the regulation of genomic functions, including gene expression that are brought about by changes in DNA methylation and/or histone tail modifications. These two epigenetic mechanisms work in concert, with alterations in DNA modification affecting chromatin conformation and vice versa. In part epigenetic modifications are inherited, but unlike the genome itself, they are cell specific, plastic, and responsive to environmental influences.

 

Differential post-translational modifications of histone tails by lysine acetylation and methylation, phosphorylation and recently also crotonylation make up the epigenetic code which is responsible for modulation of gene regulation in normal cell differentiation and in disease.

 

The Epigenetic probe project aims to generate well characterised tool compounds ‘probes’ against key enzymes and recognition domains involved in histone regulation of transcription and provide them freely to the scientific community to increase the knowledge of these proteins in biology and disease.

 

Susanne Müller-Knapp is the Project Manager for the Oxford site, which focuses on inhibitors involved in modification and recognition of modified lysines in histones, namely histone lysine demethylases,  Bromo- and  Tudor domain containing proteins. Bromodomains are small protein recognition domains, which mainly bind acetylated lysine, whereas Tudor domains recognize methylated lysine. Histone demethylases are the most recent family of histone-modifying enzymes discovered that remove methyl groups from the terminal amine of histone lysine residues. 

 

The group establishes and runs cell based assays for the different epigenetic targets to test the in vitro characterised tool compounds for cellular activity.

Group Members
Susanne Müller-Knapp

Susanne Müller-Knapp studied Human Biology in Marburg, Germany where she did her MSc in the laboratory of Miguel Beato.  She received her PhD in Molecular Biology at the Karolinska Institute in Stockholm under joined supervision of Kleanthis G. Xanthopoulos, C.I.Edvard Smith and Paschalis Sideras. Susanne stayed for a first postdoctoral period in Stockholm in the laboratory of Sven Pettersson working on the role of NFkB in inflammatory bowel disease. From 1999-2004 she worked as postdoctoral researcher at the DIBIT San Raffaele Scientific Institute in Milan, Italy in the group of Marco Bianchi analysing the function of the chromatin binding protein HMGB1 and its role in inflammation.

Since 2004 Susanne is working at the SGC, Oxford, first in the role as Scientific Coordinator and since 2010 as Project Manager of the Epigenetic probe project

, an international public private partnership that comprises 4 international pharma companies (GSK, Pfizer, Novartis and Ely Lilly), the NIH screening centres, Chris Schofield and Rob Klose from the University of Oxford (link web page) and a large network of academic and industrial collaborators.

In addition Susanne is work page coordinator for the EU grant “Affinomics” which aims to generate antibodies against 1000 targets.

She also heads the cell based assay group establishing assays for testing inhibitors against Bromodomains and histone lysine demethylases.

Martin Philpott
Clarence Yapp
Tracy Keates
Publications

 

 

 SGC Publications

 

Müller S, Filippakopoulos P, Knapp S. (2011)

Bromodomains as therapeutic targets

ERMM in press

 

Picaud, SS, Kavanagh, KL, Yue, W W, Lee, WH, Müller-Knapp S, Gileadi, O, Sacchettini, J Oppermann, U. (2011).

Structural basis of fumarate hydratase deficiency.

J Inherited Metabol. Disease. 34(3), 671-676

 

Müller S and Knapp S. (2010).

Targeting kinases for the treatment of inflammatory disease.

Expert Opinion in Drug Discovery 5, 867-881.

 

Müller S, Weigelt, J. (2010)

Open-access public-private partnerships to enable drug discovery--new approaches.

iDrugs 13(3),175-80

 

Fedorov, O, Müller S, Knapp S. (2010)

The (un)targeted cancer kinome.

Nat. Chem. Biol. 6(3),166-169.

 

Filippakopoulos P, Müller S, Knapp S. (2009)

SH2 domains: modulators of nonreceptor tyrosine kinase activity.

Curr Opin Struct Biol. 19(6),643-9.

 

Müller S, Knapp S. (2009)

Out of the box binding determines specificity of SH2 domain interaction.

Structure. 17(8),1040-1.

 

Barr, AJ Ugochukwu, E, Lee, WH, King, O, Filippakopoulos, P, Müller S, Knapp, S. (2009).

Large-scale structural analysis of the classical human protein tyrosine phosphatome.

Cell.136(2), 352-63.

 

Gileadi O, Knapp S, Lee WH, Marsden BD, Müller S, Niesen FH, Kavanagh KL, Ball LJ, von Delft F, Doyle DA, Oppermann UC, Sundström M. (2007).

The scientific impact of the Structural Genomics Consortium: a protein family and ligand-centered approach to medically-relevant human proteins.

J Struct Funct Genomics. 8(2-3), 107-19.

 

Bunkoczi G, Salah E, Filippakopoulos P, Fedorov O, Müller S, Sobott F, Parker SA, Zhang H, Min W, Turk BE, Knapp S. (2007).

Structural and functional characterization of the human protein kinase ASK1.

Structure. 15(10), 1215-26.

 

Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. (2007)

A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.

Proc Natl Acad Sci U S A. 104(51), 20523-8.

 

 

 


Pre-SGC Publications

 

Sitia G, Iannacone M, Müller S, Bianchi ME, Guidotti LG. (2007).

Treatment with HMGB1 inhibitors diminishes CTL-induced liver disease in HBV transgenic mice.

J Leukoc Biol. 81,100-7.

 

Limana F, Germani A, Zacheo A, Kajstura J, Di Carlo A, Borsellino G, Leoni O, Palumbo R, Battistini L, Rastaldo R, Müller S, Pompilio G, Anversa P, Bianchi ME, Capogrossi MC. (2005).

Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-kit+ cell proliferation and differentiation.

Circ Res. 97, 73-83.

 

Knapp, S, Müller, S, Digilio, G, Comelli, L, Bonaldi, T, Bianchi, ME, Musco, G. (2004).

The long acidic tail of high mobility group box 1 (HMGB1) protein forms an extended and flexible structure that interacts with specific residues within and between the HMG boxes.

Biochemistry 43, 11992-11997

 

Rovere-Querini, P, Capobianco, A, Scaffidi, P, Valentinis, B, Catalanotti, F, Giazzon, M, Dumitriu, IE, Müller, S, Iannacone, M, Traversari, C, Bianchi, ME, Manfredi, AA. (2004)

HMGB1 is an endogenous immune adjuvant released by necrotic cells.

EMBO Rep. 8, 825-830.

 

Müller, S, Ronfani, L, Bianchi ME. (2004)

Regulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function.

J. Int. Med. 255, 332-343

 

Agresti, A, Lupo, R, Bianchi, ME, Müller, S. (2003)

HMGB1 interacts differentially with members of the Rel family of transcription factors.

Biochem Biophys Res Commun, 302(2), 421-426.

 

Müller, S, Bianchi, ME, Knapp S. (2001).

Thermodynamics of HMGB1 interaction with duplex DNA.

Biochemistry 34,1 0254-61

 

Müller, S, Scaffidi, P, Degryse, B, Bonaldi, T, Ronfani, L, Agresti, A, Beltrame, M, Bianchi ME. (2001).

The double life of HMGB1 chromatin protein: architectural factor and extracellular signal.

EMBO J. 20, 4337-4340.

 

Degryse, B, Bonaldi, T, Scaffidi, P, Müller, S, Resnati, M, Arrigoni, G, Bianchi, ME. (2001).

The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells.

J Cell Biol. 152, 1197-206.

 

Chauveau, C, Jansson, E, Müller, S, Cogne, M, Pettersson, S. (1999).

Cutting edge: Ig heavy chain 3' HS1-4 directs correct spatial position-independent expression of a linked transgene to B lineage cells.

J. Immunol. 163, 4637-4641

 

Müller, S, Maas, A, Islam, CT, Sideras, P, Suske, G, Philipsen, S, Xanthopoulos, KG, Hendricks, RW, Smith, CIE. (1999).

Synergistic activation of the human Btk promoter by transcription factors Sp1/3 and PU.1.

Biochem. Biophys. Res. Comm. 259, 364-369

 

Smith, CIE, Bäckesjö, M, Berglöf, A, Brandén, L, Islam, T, Mattsom, PT, Mohamed, AJ, Müller, S, Nore, B, Vihinen, M (1998).

X-linked agammaglobulinemia: lack of mature B lineage cells caused by mutations in the Btk kinase.

Springer Seminars in Immunopathology 19, 369-381

 

Müller, S, Sideras, P, Smith, CIE Xanthopoulos, KG. (1996).

Cell specific expression of human Bruton's agammaglobulinemia tyrosine kinase gene (Btk) is regulated by Sp1- and Spi-1/PU.1-family members.

Oncogene 13, 1955-1964.

 

Khan, WN, Alt, FW, Gerstein, RM, Malynn, BA, Larsson, I, Rathbun, G, Davidson, L, Müller, S, Kantor, AB, Herzenberg, LA, Rosen, FS, Sideras, P. (1995).

Defective B cell development and function in Btk-deficient mice.

Immunity 3, 283-299.

 

Vorechovski, I, Vihinen, M, de Saint Basile, G, Honsova, S, Hammarström, L, Müller, S, Nilsson, L, Fischer, A, Smith, CIE. (1995).

DNA-based mutation analysis of Bruton's tyrosine kinase gene in patients with X-linked agammaglobulinaemia.

Hum. Mol. Gen. 4, 51-58.

 

Sideras, P* and Müller, S,* Shiels, H, Jin, H, Khan, WN, Nilsson, L, Parkinson, E, Thomas, JD, Branden, L, Larsson, I, Paul, WE, Rosen, FS, Alt, JD, Vetrie, D, Smith, CIE, Xanthopoulos, KG. (1994).

Genomic organization of mouse and human Bruton's agammaglobulinemia tyrosine kinase (Btk) loci.

J.Immunol. 153, 5607-5617.

* shared first authorship

 

Hagen, G, Müller, S, Beato, M,  Suske G. (1994).

Sp1-mediated transcriptional activation is repressed by Sp3.

EMBO J. 13, 3843-3851

 

Hagen, G., Müller, S., Beato, M. and Suske, G. (1992).

Cloning by recognition site screening of two novel GT box binding proteins: a family of Sp1 related genes.

Nucleic Acids Res. 20, 5519-5525.

 

Contact

susanne [dot] muller-knapp[at]sgc [dot] ox [dot] ac [dot] uk (Dr. Susanne Muller)

SGC
University of Oxford
Old Road Campus REsearch Building
Roosevelt Drive
Headington
Oxford
OX3 7DQ
UK

Phone: +44 1865 617587