Epigenetics and Cellular Biology

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

Catherine Rogers
Clarence Yapp

Clarence is currently a Post-doctoral Research Scientist under Dr. Susanne Müller-Knapp at the Target Discovery Institute and Structural Genomics Consortium. His work focuses on developing high-content cellular assays for identifying potent inhibitiors against chromatin modifiers such as demethylases and bromodomains. In 2013, he was awarded a grant from the Medical Research Fund to further develop FRAP, one of the SGC's most successful cellular assays to date.  He is also Head of Microscopy at the Botnar Research Centre where he collaborates extensively with the group of Professor Udo Oppermann. His other collaborative research interests include:

a) identifying single molecule interactions by super-resolution microscopy or fluorescence correlation spectroscopy (with the Ludwig Institute for Cancer Research and the Kennedy Institute of Rheumatology)

b) visualizing extracellular matrices in 3D tissues by non-linear optical imaging (with the Botnar Research Centre)

c) using two-photon lasers to temporarily permeabilize cells (a technique called optoporation) for the purpose of delivering ‘cargo’ into cells without the need for fixatives (with the Wellcome Trust Centre for Human Genetics)

Stephanie Hatch
Vicki Gamble
Vita Fedele

Group Publications


CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses.
Hammitzsch, A; Tallant, C; Fedorov, O; O'Mahony, A; Brennan, PE; Hay, DA; Martinez, FO; Al-Mossawi, MH; de Wit, J; Vecellio, M; Wells, C; Wordsworth, P; Müller, S; Knapp, S; Bowness, P;
Proceedings of the National Academy of Sciences of USA. 2015 112:10768-10773. doi: 10.1073/pnas.1501956112
PMID: 26261308

Design and synthesis of potent and selective inhibitors of BRD7 and BRD9 bromodomains
Hay, DA; Rogers, CM; Fedorov, O; Tallant, C; Martin, S; Monteiro, OP; Mueller, S; Knapp, S; Schofield, CJ; Brennan, PE;
MedChemComm. 2015 6:1381-1386. doi: 10.1039/c5md00152h

Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF.
Bennett, JM; Fedorov, O; Tallant, C; Monteiro, OP; Meier, J; Gamble, V; Savitski, P; Nunez-Alonso, GA; Haendler, B; Rogers, C; Brennan, PE; Müller, S; Knapp, S;
Journal of Medicinal Chemistry. 2015 :-. doi: 10.1021/acs.jmedchem.5b00458
PMID: 25974391

Identification of Covalent Bromodomain Binders through DNA Display of Small Molecules.
Daguer, JP; Zambaldo, C; Abegg, D; Barluenga, S; Tallant, C; Müller, S; Adibekian, A; Winssinger, N;
Angewandte Chemie International Edition. 2015 54:6057-6061. doi: 10.1002/anie.201412276
PMID: 25772490

LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor.
Clark, PG; Vieira, LC; Tallant, C; Fedorov, O; Singleton, DC; Rogers, CM; Monteiro, OP; Bennett, JM; Baronio, R; Müller, S; Daniels, DL; Méndez, J; Knapp, S; Brennan, PE; Dixon, DJ;
Angewandte Chemie International Edition. 2015 54:6217-6221. doi: 10.1002/anie.201501394
PMID: 25864491

Discovery and characterization of GSK2801, a selective chemical probe for the bromodomains BAZ2A and BAZ2B.
Chen, P; Chaikuad, A; Bamborough, P; Bantscheff, M; Bountra, C; Chung, CW; Fedorov, O; Grandi, P; Jung, D; Lesniak, R; Lindon, M; Müller, S; Philpott, M; Prinjha, RK; Rogers, CM; Selenski, C; Tallant, C; Werner, T; Willson, TM; Knapp, S; Drewry, DH;
Journal of Medicinal Chemistry. 2015 :-. doi: 10.1021/acs.jmedchem.5b00209
PMID: 25799074

Structure enabled design of BAZ2-ICR, a chemical probe targeting the bromodomains of BAZ2A and BAZ2B.
Drouin, L; McGrath, S; Vidler, LR; Chaikuad, A; Monteiro, O; Tallant, C; Philpott, M; Rogers, C; Fedorov, O; Liu, M; Akhtar, W; Hayes, A; Raynaud, F; Müller, S; Knapp, S; Hoelder, S;
Journal of Medicinal Chemistry. 2015 58:2553-2559. doi: 10.1021/jm501963e
PMID: 25719566


Dual kinase/bromodomain inhibitors for rationally designed polypharmacology
Quinn, ER; Ciceri, P; Mueller-Knapp, S; O'Mahony, A; Fedorov, O; Filippakopoulos, P; Hunt, JP; Lasater, EA; Pallares, G; Picaud, S; Wells, C; Wodicka, LM; Shah, NP; Knapp, S; Treiber, DK;
Cancer Research. 2014 74:-. doi: 10.1158/1538-7445.AM2014-5387

Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains.
Hay, DA; Fedorov, O; Martin, S; Singleton, DC; Tallant, C; Wells, C; Picaud, S; Philpott, M; Monteiro, OP; Rogers, CM; Conway, SJ; Rooney, TP; Tumber, A; Yapp, C; Filippakopoulos, P; Bunnage, ME; Müller, S; Knapp, S; Schofield, CJ; Brennan, PE;
Journal of the American Chemical Society. 2014 136:9308-9319. doi: 10.1021/ja412434f
PMID: 24946055

A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-π interaction.
Rooney, TP; Filippakopoulos, P; Fedorov, O; Picaud, S; Cortopassi, WA; Hay, DA; Martin, S; Tumber, A; Rogers, CM; Philpott, M; Wang, M; Thompson, AL; Heightman, TD; Pryde, DC; Cook, A; Paton, RS; Müller, S; Knapp, S; Brennan, PE; Conway, SJ;
Angewandte Chemie International Edition. 2014 53:6126-6130. doi: 10.1002/anie.201402750
PMID: 24821300

Affinity map of bromodomain protein 4 (BRD4) interactions with the histone H4 tail and the small molecule inhibitor JQ1.
Jung, M; Philpott, M; Müller, S; Schulze, J; Badock, V; Eberspächer, U; Moosmayer, D; Bader, B; Schmees, N; Fernández-Montalván, A; Haendler, B;
Journal of Biological Chemistry. 2014 289:9304-9319. doi: 10.1074/jbc.m113.523019
PMID: 24497639

Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.
Ciceri, P; Müller, S; O'Mahony, A; Fedorov, O; Filippakopoulos, P; Hunt, JP; Lasater, EA; Pallares, G; Picaud, S; Wells, C; Martin, S; Wodicka, LM; Shah, NP; Treiber, DK; Knapp, S;
Nature Chemical Biology. 2014 10:305-312. doi: 10.1038/nchembio.1471
PMID: 24584101

Discovery of BET bromodomain inhibitors and their role in target validation
Mueller, S; Knapp, S;
MedChemComm. 2014 5:288-296. doi: 10.1039/c3md00291h

Structure of cyclin G-associated kinase (GAK) trapped in different conformations using nanobodies.
Chaikuad, A; Keates, T; Vincke, C; Kaufholz, M; Zenn, M; Zimmermann, B; Gutiérrez, C; Zhang, RG; Hatzos-Skintges, C; Joachimiak, A; Muyldermans, S; Herberg, FW; Knapp, S; Müller, S;
Biochemical Journal. 2014 459:59-69. doi: 10.1042/bj20131399
PMID: 24438162

Assessing cellular efficacy of bromodomain inhibitors using fluorescence recovery after photobleaching.
Philpott, M; Rogers, CM; Yapp, C; Wells, C; Lambert, JP; Strain-Damerell, C; Burgess-Brown, NA; Gingras, AC; Knapp, S; Müller, S;
Epigenetics and Chromatin. 2014 7:14-. doi: 10.1186/1756-8935-7-14
PMID: 25097667

[1,2,4]triazolo[4,3-a]phthalazines: inhibitors of diverse bromodomains.
Fedorov, O; Lingard, H; Wells, C; Monteiro, OP; Picaud, S; Keates, T; Yapp, C; Philpott, M; Martin, SJ; Felletar, I; Marsden, BD; Filippakopoulos, P; Müller, S; Knapp, S; Brennan, PE;
Journal of Medicinal Chemistry. 2014 57:462-476. doi: 10.1021/jm401568s
PMID: 24313754


RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain.
Picaud, S; Wells, C; Felletar, I; Brotherton, D; Martin, S; Savitsky, P; Diez-Dacal, B; Philpott, M; Bountra, C; Lingard, H; Fedorov, O; Müller, S; Brennan, PE; Knapp, S; Filippakopoulos, P;
Proceedings of the National Academy of Sciences of USA. 2013 110:19754-19759. doi: 10.1073/pnas.1310658110
PMID: 24248379

PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains.
Picaud, S; Da Costa, D; Thanasopoulou, A; Filippakopoulos, P; Fish, PV; Philpott, M; Fedorov, O; Brennan, P; Bunnage, ME; Owen, DR; Bradner, JE; Taniere, P; O'Sullivan, B; Müller, S; Schwaller, J; Stankovic, T; Knapp, S;
Cancer Research. 2013 73:3336-3346. doi: 10.1158/0008-5472.can-12-3292
PMID: 23576556

Inhibition of BET Bromodomain Targets Genetically Diverse Glioblastoma
Cheng, Z; Gong, Y; Ma, Y; Lu, K; Lu, X; Pierce, LA; Thompson, RC; Muller, S; Knapp, S; Wang, J;
Clinical Cancer Research. 2013 19:1748-1759. doi: 10.1158/1078-0432.CCR-12-3066


Epigenetic chemical probes.
Müller, S; Brown, PJ;
Clinical Pharmacology and Therapeutics. 2012 92:689-693. doi: 10.1038/clpt.2012.154
PMID: 23093316

Cheng, Z; Gong, Y; Ma, Y; Ller-Knapp, SM; Knapp, S; Wang, J;
Clinical Cancer Research. 2012 14:28-28. doi:
PMID: 23403638


Structural basis of fumarate hydratase deficiency.
Picaud, S; Kavanagh, KL; Yue, WW; Lee, WH; Muller-Knapp, S; Gileadi, O; Sacchettini, J; Oppermann, U;
Journal of Inherited Metabolic Disease. 2011 34:671-676. doi: 10.1007/s10545-011-9294-8
PMID: 21445611


Targeting kinases for the treatment of inflammatory diseases
Müller, S; Knapp, S; Knapp, S;
Expert Opinion on Drug Discovery. 2010 5:867-881. doi: 10.1517/17460441.2010.504203
PMID: 22823261

Open-access public-private partnerships to enable drug discovery - New approaches
Mueller, S; Weigelt, J;
IDrugs: the Investigational Drugs Journal. 2010 13:175-180. doi:
PMID: 20191434

The (un)targeted cancer kinome.
Fedorov, O; Müller, S; Knapp, S;
Nature Chemical Biology. 2010 6:166-169. doi: 10.1038/nchembio.297
PMID: 20154661


SH2 domains: modulators of nonreceptor tyrosine kinase activity.
Filippakopoulos, P; Müller, S; Knapp, S;
Current Opinion in Structural Biology. 2009 19:643-649. doi: 10.1016/j.sbi.2009.10.001
PMID: 19926274

Out of the Box Binding Determines Specificity of SH2 Domain Interaction
Müller, S; Knapp, S; Knapp, S;
Structure. 2009 17:1040-1041. doi: 10.1016/j.str.2009.07.002
PMID: 19679083

Large-scale structural analysis of the classical human protein tyrosine phosphatome.
Barr, AJ; Ugochukwu, E; Lee, WH; King, ON; Filippakopoulos, P; Alfano, I; Savitsky, P; Burgess-Brown, NA; Müller, S; Knapp, S;
Cell. 2009 136:352-363. doi: 10.1016/j.cell.2008.11.038
PMID: 19167335


A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.
Fedorov, O; Marsden, B; Pogacic, V; Rellos, P; Müller, S; Bullock, AN; Schwaller, J; Sundström, M; Knapp, S;
Proceedings of the National Academy of Sciences of USA. 2007 104:20523-20528. doi: 10.1073/pnas.0708800104
PMID: 18077363

Structural and functional characterization of the human protein kinase ASK1.
Bunkoczi, G; Salah, E; Filippakopoulos, P; Fedorov, O; Müller, S; Sobott, F; Parker, SA; Zhang, H; Min, W; Turk, BE; Knapp, S;
Structure. 2007 15:1215-1226. doi: 10.1016/j.str.2007.08.011
PMID: 17937911

The scientific impact of the Structural Genomics Consortium: a protein family and ligand-centered approach to medically-relevant human proteins.
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;
Journal of Structural and Functional Genomics. 2007 8:107-119. doi: 10.1007/s10969-007-9027-2
PMID: 17932789

Treatment with HMGB1 inhibitors diminishes CTL-induced liver disease in HBV transgenic mice.
Sitia, G; Iannacone, M; Müller, S; Bianchi, ME; Guidotti, LG;
Journal of Leukocyte Biology. 2007 81:100-107. doi: 10.1189/jlb.0306173
PMID: 16935945


Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-kit+ cell proliferation and differentiation.
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;
Circulation Research. 2005 97:e73-e83. doi: 10.1161/01.RES.0000186276.06104.04
PMID: 16166556


HMGB1 is an endogenous immune adjuvant released by necrotic cells.
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;
EMBO Reports. 2004 5:825-830. doi: 10.1038/sj.embor.7400205
PMID: 15272298

Regulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function.
Müller, S; Ronfani, L; Bianchi, ME;
Journal of Internal Medicine. 2004 255:332-343. doi:
PMID: 14871457


HMGB1 interacts differentially with members of the Rel family of transcription factors.
Agresti, A; Lupo, R; Bianchi, ME; Müller, S;
Biochemical and Biophysical Research Communications. 2003 302:421-426. doi:
PMID: 12604365


Thermodynamics of HMGB1 interaction with duplex DNA.
Müller, S; Bianchi, ME; Knapp, S;
Biochemistry. 2001 40:10254-10261. doi:
PMID: 11513603

New EMBO members' review: the double life of HMGB1 chromatin protein: architectural factor and extracellular signal.
Müller, S; Scaffidi, P; Degryse, B; Bonaldi, T; Ronfani, L; Agresti, A; Beltrame, M; Bianchi, ME;
The EMBO Journal. 2001 20:4337-4340. doi: 10.1093/emboj/20.16.4337
PMID: 11500360

The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells.
Degryse, B; Bonaldi, T; Scaffidi, P; Müller, S; Resnati, M; Sanvito, F; Arrigoni, G; Bianchi, ME;
The Journal of Cell Biology. 2001 152:1197-1206. doi:
PMID: 11257120


Synergistic activation of the human Btk promoter by transcription factors Sp1/3 and PU.1.
Müller, S; Maas, A; Islam, TC; Sideras, P; Suske, G; Philipsen, S; Xanthopoulos, KG; Hendriks, RW; Smith, CI;
Biochemical and Biophysical Research Communications. 1999 259:364-369. doi: 10.1006/bbrc.1999.0677
PMID: 10362515


X-linked agammaglobulinemia: lack of mature B lineage cells caused by mutations in the Btk kinase.
Smith, CI; Bäckesjö, CM; Berglöf, A; Brandén, LJ; Islam, T; Mattsson, PT; Mohamed, AJ; Müller, S; Nore, B; Vihinen, M;
Springer Seminars in Immunopathology. 1998 19:369-381. doi:
PMID: 9618763



Defective B cell development and function in Btk-deficient mice.
Khan, WN; Alt, FW; Gerstein, RM; Malynn, BA; Larsson, I; Rathbun, G; Davidson, L; Müller, S; Kantor, AB; Herzenberg, LA;
Immunity. 1995 3:283-299. doi:
PMID: 7552994

DNA-based mutation analysis of Bruton's tyrosine kinase gene in patients with X-linked agammaglobulinaemia.
Vorechovský, I; Vihinen, M; de Saint Basile, G; Honsová, S; Hammarström, L; Müller, S; Nilsson, L; Fischer, A; Smith, CI;
Human Molecular Genetics. 1995 4:51-58. doi:
PMID: 7711734


Genomic organization of mouse and human Bruton's agammaglobulinemia tyrosine kinase (Btk) loci.
Sideras, P; Müller, S; Shiels, H; Jin, H; Khan, WN; Nilsson, L; Parkinson, E; Thomas, JD; Brandén, L; Larsson, I;
Journal of Immunology. 1994 153:5607-5617. doi:
PMID: 7989760

Sp1-mediated transcriptional activation is repressed by Sp3.
Hagen, G; Müller, S; Beato, M; Suske, G;
The EMBO Journal. 1994 13:3843-3851. doi:
PMID: 8070411


Cloning by recognition site screening of two novel GT box binding proteins: a family of Sp1 related genes.
Hagen, G; Müller, S; Beato, M; Suske, G;
Nucleic Acids Research. 1992 20:5519-5525. doi:
PMID: 1454515


HMGB1 protein inhibitors and/or antagonists for the treatment of vascular diseases.
Muller-Knapp, S; Bianchi, ME; Bonaldi, T; Scaffidi, P; Degryse, B;
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