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Epigenetics and Cellular Biology

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 8 international pharma companies, 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.

Hannah Lingard

Hannah Lingard studied Natural Sciences at Churchill College, Cambridge (graduating in 2006) and began a PhD there under the supervision of Dr Martin Smith, working on cascade approaches to decahydroquinoline ring systems. In 2008 the Smith group moved to Oxford so she completed her DPhil in 2010 at Brasenose College, Oxford. Following this she worked for two years as a postdoc in the lab of Professor Andrew Hamilton, FRS, on molecular switches and beta-sheet mimics. She joined the SGC as Scientific Coordinator – Epigenetics in September 2012.

Publications:

  1. Ian M. Jones, Hannah Lingard and Andrew D. Hamilton – ‘pH-Dependent Conformational Switching in 2,6-Benzamidodiphenylacetylenes’. Angew. Chem. Int. Ed., 2011, 50 (52), pp. 12569-12571.
  2. David J. Fox, Jill Reckless, Hannah Lingard, Stuart Warren and David J. Grainger – ‘Highly Potent, Orally Available Anti-inflammatory Broad Spectrum Chemokine Inhibitors’. J. Med. Chem., 2009, 52 (11), pp. 3591-3595.
  3. Hannah Lingard, James Luccarelli, Amber L. Thompson, Richard T. W. Scott, Sam Thompson and Andrew D. Hamilton – ‘Diphenylacetylene-linked peptide strands induce directional β-sheet formation’, Submitted.
  4. Susanne Müller, Hannah Lingard and Stefan Knapp – ‘Selective Inhibition of Acetyl-Lysine Effector Domains of the Bromodomain Family in Oncology’. Signaling Pathways and Targeting Transcription in Cancer, 2012
Martin Philpott
Clarence Yapp
Christopher Wells
Dalia Barsyte-Lovejoy

Dalia’s PhD work in molecular cell biology and toxicology was carried out at the University of Manchester (UK). In her postdoctoral training at the University of Manchester and Ontario Cancer Institute, she investigated mechanisms of MAPK signaling in stress response and c-Myc oncogene driven transcriptional programs associated with cellular stress and epigenetics.  Working for Protagenic Therapeutics Canada Inc, Dalia specialized in neuropeptide cellular signaling mechanisms in CNS diseases. She is an author of over 40 scientific publications and her interests include transcriptional and epigenetic programs that influence cell homeostasis, differentiation and carcinogenesis.

Publications
SGC Publications
Müller S, Brown PJ. (2012).
Clin Pharmacol Ther. 92(6):689-93.

 

Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Müller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S. (2012).
Cell. 149(1),214-31

 

Müller S, Filippakopoulos P, Knapp S. (2011).
ERMM 13:e29
 
Picaud, SS, Kavanagh, KL, Yue, W W, Lee, WH, Müller-Knapp S, Gileadi, O, Sacchettini, J Oppermann, U. (2011).
J Inherited Metabol. Disease. 34(3), 671-676

 

Müller S and Knapp S. (2010).
Expert Opinion in Drug Discovery 5, 867-881.

 

Müller S, Weigelt, J. (2010).
iDrugs 13(3),175-80

 

Fedorov, O, Müller S, Knapp S. (2010).
Nat. Chem. Biol. 6(3),166-169.

 

Filippakopoulos P, Müller S, Knapp S. (2009).
Curr Opin Struct Biol. 19(6),643-9.

 

Müller S, Knapp S. (2009).
Structure. 17(8),1040-1.

 

Barr, AJ Ugochukwu, E, Lee, WH, King, O, Filippakopoulos, P, Müller S, Knapp, S. (2009).
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).
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).
Structure. 15(10), 1215-26.

 

Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. (2007)
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).
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).
Circ Res. 97, 73-83.

 

Knapp, S, Müller, S, Digilio, G, Comelli, L, Bonaldi, T, Bianchi, ME, Musco, G. (2004).
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)
EMBO Rep. 8, 825-830.

 

Müller, S, Ronfani, L, Bianchi ME. (2004)
J. Int. Med. 255, 332-343

 

Agresti, A, Lupo, R, Bianchi, ME, Müller, S. (2003)
Biochem Biophys Res Commun, 302(2), 421-426.

 

Müller, S, Bianchi, ME, Knapp S. (2001).
Biochemistry 34,1 0254-61

 

Müller, S, Scaffidi, P, Degryse, B, Bonaldi, T, Ronfani, L, Agresti, A, Beltrame, M, Bianchi ME. (2001).
EMBO J. 20, 4337-4340.

 

Degryse, B, Bonaldi, T, Scaffidi, P, Müller, S, Resnati, M, Arrigoni, G, Bianchi, ME. (2001).
J Cell Biol. 152, 1197-206.

 

Chauveau, C, Jansson, E, Müller, S, Cogne, M, Pettersson, S. (1999).
J. Immunol. 163, 4637-4641

 

Müller, S, Maas, A, Islam, CT, Sideras, P, Suske, G, Philipsen, S, Xanthopoulos, KG, Hendricks, RW, Smith, CIE. (1999).
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).
Springer Seminars in Immunopathology 19, 369-381

 

Müller, S, Sideras, P, Smith, CIE Xanthopoulos, KG. (1996).
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).
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).
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).
J.Immunol. 153, 5607-5617.
* shared first authorship

 

Hagen, G, Müller, S, Beato, M,  Suske G. (1994).
EMBO J. 13, 3843-3851

 

Hagen, G., Müller, S., Beato, M. and Suske, G. (1992).
Nucleic Acids Res. 20, 5519-5525.
 
Contact

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

Phone: +44 1865 617587