WIMM PI Curriculum Vitae

Personal Data Name Richard Gibbons Nationality UK Email [email protected]

Present Position 1997-present Honorary Consultant in Clinical Genetics (Oxford Trust) 2010-present Professor of Clinical Genetics (University of Oxford) 2001-present Group Head, MRC Molecular Haematology Unit (WIMM)

Previous Positions 1980 DPhil Student, University of Oxford.

1990 Action Research Training Fellow, University of Oxford.

1995 Wellcome Advanced Training Fellow, University of Oxford.

1997 University Lecturer in Clinical Biochemistry, University of Oxford.

Research Achievements

Over the last 20 years I have worked to understand the role of a chromatin remodelling protein in transcriptional regulation and how, when mutated, it leads to human disease. ATRX is a member of the SWI2/SNF2 family of molecular motors which remodel chromatin by using the hydrolysis of ATP as an energy source. Mutations in ATRX give rise to a syndromal form of mental retardation associated with alpha thalassaemia (ATR-X syndrome). ATR-X represents one of the best studied examples of a newly recognised class of human disease, a disease of chromatin.

My notable achievements have been:

1. Characterisation of ATR-X syndrome (JMed Genet 1991; AJMG 1995)

2. Mapping and positionaL cloning of the ATRX gene (ASHG 1992; Cell 1995)).

3. Establishing an international referral centre for ATR-X syndrome offering diagnostic tests as well as identification of disease causing mutations and provision of carrier and prenatal testing.

4. Identification of acquired somatic mutations in ATRX in the alpha thalassaemia myelodysplastia syndrome (Nat Genet 2003).

5. Defining the key functional regions of the ATRX protein and determining how mutations affect structure and function (Nat Genet 1997; PNAS 2007; Hum Mut 2008; PNAS 2011)

6. Determining a critical interacting partner, Daxx (PNAS 2003)

7. Generating a mouse knockout model for the ATRX gene. This has been used to show how mutations in ATRX lead to skewed X inactivation. It has also indicate that ATRX plays a role with Daxx in inserting the histone variant H3.3 into telomeric DNA (Plos Genet 2006; AJHG 2007; Cell 2010)

8. Demonstrated that ATRX protein targets tandem repeats and influences allele-specific expression of near by genes in a size dependent manner explaining the phenotypic variation observed in ATR-X syndrome (Cell 2010).

Lay Summary of Research

Despite the revolution in genetics in the last decade and in particular the sequencing of the human genome, the regulation of gene expression largely remains a mystery. Every cell of the body contains a full complement of genes but only expresses a small repertoire required for that tissues function, such as the oxygen carrying protein, haemoglobin, in red blood cells. A complex hierarchy of regulation is emerging involving tissue-specific signals, chemical modifications to the DNA molecule and the proteins about which DNA is wrapped, enzymes that package and unpackage DNA and different cellular compartments that either favour or repress gene expression. Human genetic diseases are now being identified in which the components of this complex apparatus are disrupted. In one such condition, ATR-X syndrome, the affected children have profound learning difficulties, a characteristic facial appearance, abnormalities of genital development and a form of anaemia. It arises because of mutations in a protein involved in the regulation of gene expression. The diverse problems probably reflect the many different genes whose expression is perturbed. The overall aim of this programme is to determine the role of such proteins in the regulation of gene expression and their involvement in human disease. All Publications Over the Past 5 Years Gibbons RJ (2008) Epigenetics and its genetic syndromes. In: Epigenetics in Biology and Medicine (ed. by Esteller M). Taylor & Francis. Gibbons RJ, Wada T, Fisher CA, Malik N, Mitson MJ, Steensma DP, Fryer A, Goudie DR, Krantz ID & Traeger-Synodinos J (2008) Mutations in the chromatin-associated protein ATRX. Human mutation, 29, 796-802. Seah C, Levy MA, Jiang Y, Mokhtarzada S, Higgs DR, Gibbons RJ & Berube NG (2008) Neuronal death resulting from targeted disruption of the Snf2 protein ATRX is mediated by p53. J Neurosci, 28, 12570-12580. Garrick D, De Gobbi M, Gibbons R & Higgs DR (2009) Research Highlights: News and Views. Epigenomics, 1, 231-234. Haas PS, Roy NB, Gibbons RJ, Deville MA, Fisher C, Schwabe M, Bisse E, van Dorsselaer A, Higgs DR & Lubbert M (2009) The role of X-inactivation in the gender bias of patients with acquired alpha-thalassaemia and myelodysplastic syndrome (ATMDS). Br J Haematol, 144, 538-545. Higgs DR, Buckle VJ, Gibbons RJ & Steensma D (2009) Unusual types of a thalassemia. In: Disorders of Hemoglobin (ed. by Steinberg MH, Forget BG, Higgs DR & Weatherall DJ), pp. 296-320. Cambridge University Press, Cambridge. Jezela-Stanek A, Fisher C, Szarras-Czapnik M, Olczak-Kowalczyk D, Gibbons RJ, Slowikowska-Hilczer J & Krajewska-Walasek M (2009) X-linked alpha thalassaemia/mental retardation syndrome: a case with gonadal dysgenesis, caused by a novel mutation in ATRX gene. Clin Dysmorphol, 18, 168-171. Lower KM, Hughes JR, De Gobbi M, Henderson S, Viprakasit V, Fisher C, Goriely A, Ayyub H, Sloane-Stanley J, Vernimmen D, Langford C, Garrick D, Gibbons RJ & Higgs DR (2009) Adventitious changes in long-range gene expression caused by polymorphic structural variation and promoter competition. Proc Natl Acad Sci U S A, 106, 21771-21776. Medina CF, Mazerolle C, Wang Y, Berube NG, Coupland S, Gibbons RJ, Wallace VA & Picketts DJ (2009) Altered visual function and interneuron survival in Atrx knockout mice: inference for the human syndrome. Hum Mol Genet, 18, 966-977. Gibbons RJ (2010) ATR-X. In: Management of Genetic Syndromes (ed. by Cassidy S & Allanson J), pp. 97-110. John Wiley & Sons. Gibbons RJ & Higgs DR (2010) ATRX: Taming tandem repeats. Cell Cycle, 9, 4605-4606. Goldberg AD, Banaszynski LA, Noh KM, Lewis PW, Elsaesser SJ, Stadler S, Dewell S, Law M, Guo X, Li X, Wen D, Chapgier A, DeKelver RC, Miller JC, Lee YL, Boydston EA, Holmes MC, Gregory PD, Greally JM, Rafii S, Yang C, Scambler PJ, Garrick D, Gibbons RJ, Higgs DR, Cristea IM, Urnov FD, Zheng D & Allis CD (2010) Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell, 140, 678-691. Higgs DR & Gibbons RJ (2010) The molecular basis of alpha-thalassemia: a model for understanding human molecular genetics. Hematol Oncol Clin North Am, 24, 1033-1054. Law MJ, Lower KM, Voon HP, Hughes JR, Garrick D, Viprakasit V, Mitson M, De Gobbi M, Marra M, Morris A, Abbott A, Wilder SP, Taylor S, Santos GM, Cross J, Ayyub H, Jones S, Ragoussis J, Rhodes D, Dunham I, Higgs DR & Gibbons RJ (2010) ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size- dependent manner. Cell, 143, 367-378. De Gobbi M, Garrick D, Lynch M, Vernimmen D, Hughes JR, Goardon N, Luc S, Lower KM, Sloane-Stanley JA, Pina C, Soneji S, Enver T, Renella R, Taylor S, Jacobsen SEW, Vyas P, Gibbons RJ & Higgs DR (2011) Generation of bivalent chromatin domains during cell fate decisions. Epigenetics & Chromatin, 4, 9. Eustermann S, Yang J-C, Law MJ, Amos RJ, Chapman LM, Jelinska C, Garrick D, Clynes D, Gibbons RJ, Rhodes D, Higgs DR & Neuhaus D (2011) Combinatorial readout of histone H3 modifications specifies localisation of ATRX to heterochromatin. Nat Struct Mol Biol, 18, 777-782. Giardine B, Borg J, Higgs DR, Peterson KR, Philipsen S, Maglott D, Singleton BK, Anstee DJ, Basak AN, Clark B, Costa FC, Faustino P, Fedosyuk H, Felice AE, Francina A, Gallivan MVE, Georgitsi M, Gibbons RJ, Giordano PC, Harteveld CL, Hoyer JD, KJoly P, Kanavakis E, Kollia P, Menzel S, Miller W, Moradkhani K, Old J, Papachatzopoulou A, Papadakis MN, Papadopoulos P, Pavlovic S, Radmilovic M, Riemer C, Schrijver I, Stojilijkovic M, Thein SL, Traeger-Synodinos JT, R., Wada T, Waye JS, Wiemann C, Zukic B, Chui DHK, Wajcman H, Hardison RC & Patrinos GP (2011) Systemic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach. Nat Genet, 43, 295-301. Lynch MD, Smith AJH, De Gobbi M, Flenley M, Hughes JR, Vernimmen D, Ayyub H, Sharpe JA, Sloane-Stanley JA, Sutherland L, Meek S, Burdon T, Gibbons RJ, Garrick D & Higgs DR (2011) An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate Polycomb complex recruitment. EMBO J, 31, 317-329. Mitson M, Kelley LA, Sternberg MJ, Higgs DR & Gibbons RJ (2011) Functional significance of mutations in the Snf2 domain of ATRX. Hum Mol Genet, 20, 2603-2610. Hughes JR, Lower KM, Dunham I, Taylor S, De Gobbi M, Sloane-Stanley JA, Reittie JE, McGowan SJ, Gregory L, Ragoussis J, Vernimmen D, Zhao Y, Jones S, Birney E, Gibbons RJ & Higgs DR (2012) Comprehensive, high resolution analysis of cis-acting regulatory networks using a modified 4C protocol and high throughput sequencing. In preparation. Kowalczyk M, S., Babbs C, Sanchez-Pulido L, Dorota Szumska D, Hughes JR, Sharpe JA, Sloane-Stanley JA, Morriss-Kay GM, Smoot LB, Roberts AE, Watkins H, Bhattacharya S, Gibbons RJ, Ponting CP, Wood WG & Higgs DR (2012) Nprl3 is required for normal development of the cardiovascular system. Mammalian Genome, 23:404-15 Kowalczyk MS, Hughes JR, Garrick D, Lynch MD, Sharpe JA, Sloane-Stanley JA, McGowan SJ, De Gobbi M, Hosseini M, Vernimmen D, Brown JM, Gray NE, Collavin L, Gibbons RJ, Flint J, Taylor S, Buckle VJ, Milne TA, Wood WG & Higgs DR (2012) Intragenic Enhancers Act as Alternative Promoters. Molecular cell, 45, 447-458. Gibbons, R.J. (2012) Alpha Thalassemia, mental retardation and myelodysplastic syndrome. Cold Spring Harb Perspect Med 2 (10). Lower KM, De Gobbi M, Hughes JR, Derry CJ, Ayyub H, Sloane-Stanley JA, Vernimmen D, Garrick D, Gibbons RJ, Higgs DR. (2013) Analysis of Sequence Variation Underlying Tissue-specific Transcription Factor Binding and Gene Expression. Hum. Molec. Genet. 34:1140-8 Hughes JR, Lower KM, Dunham I, Taylor S, De Gobbi M, Sloane-Stanley JA, McGowan S, Ragoussis J, Vernimmen D, Gibbons RJ, Higgs DR. (2013) High-resolution analysis of cis- acting regulatory networks at the α-globin locus. Philos Trans R Soc Lond B Biol Sci. 368(1620):20120361 Clynes D, Gibbons RJ. (2013) ATRX and the replication of structured DNA. Curr Opin Genet Dev 23:289-94 Clynes D, Higgs DR and Gibbons RJ. (2013) The chromatin remodeller ATRX: a repeat offender in human disease. Trends Biochem Sci 38:461-6 Qiao Y, Mondal K, Trapani V, Wen J, Carpenter G, Wildin R, Price EM, Gibbons RJ, Eichmeyer J, Jiang R, Dupont B, Martell S, Lewis SM, Robinson WP,O'Driscoll M, Wolf FI, Zwick ME, Rajcan-Separovic E. (2013) Variant ATRX Syndrome with Dysfunction of ATRX and MAGT1 Genes. Hum Mutat. (in press)

Ten Key Publications Throughout your Career Gibbons RJ, Suthers GK, Wilkie AOM, Buckle VJ, Higgs DR. (1992). X linked  thalassemia/mental retardation (ATR-X) syndrome: localization to Xq12-21.31 by X inactivation and linkage analysis. Am J Hum Genet 51, 1136-1149. Gibbons, R.J., Picketts, D.J., Villard, L. and Higgs, D.R. (1995) X-linked mental retardation associated with  thalassemia (ATR-X syndrome) results from mutations in a putative global transcriptional regulator. Cell 80, 837-845 Gibbons RJ, Bachoo S, Picketts DJ, Aftimos S, Asenbauer B, Bergoffen J, Berry SA, Dahl N, Fryer A, Keppler K, Kurosawa K, Levin ML, Masuno M, Neri G, Pierpont ME, Slaney SF, Higgs DR. (1997). Mutations in transcriptional regulator hATRX establish the functional significance of a PHD-like domain. Nature Genet. 17, 146-148 Gibbons, R.J., McDowell,T.L., Raman, S., O'Rourke,D.M., Garrick, D., Ayyub, H. and Higgs, D.R. (2000) Mutations in the human SWI/SNF-like protein ATRX cause widespread changes in the pattern of DNA methylation. Nature Genet. 24, 368-371 Gibbons RJ, Pellagatti A, Garrick D, Wood WG, Malik N, Ayyub H, Langford C, Boultwood J, Wainscoat JS, Higgs DR. (2003) Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS). Nat.Genet. 34, 446-449 Xue, Y., Gibbons, R.J., Yang, D., McDowell, T.L., Sechi, S., Qin, J., Zhou, S., Higgs, D.H. and Wang, W. (2003) The ATRX syndrome protein forms a new chromatin-remodelling complex with Daxx and localizes in PML nuclear bodies. PNAS 100, 10635-40 David Garrick , Jackie A. Sharpe, Ruth Arkell, Lorraine Dobbie, Andrew J. Smith, William G. Wood, Douglas R. Higgs and Richard J. Gibbons (2006) Loss of Atrx Affects Trophoblast Development and the Pattern of X-inactivation in Extra-embryonic Tissues PloS Genetics 2: e58 Mary R. Muers , Jacqueline A. Sharpe , David Garrick , Jacqueline Sloane-Stanley , Patrick M. Nolan , Terry Hacker , William G. Wood , Douglas R. Higgs and Richard J. Gibbons (2007) Defining the cause of skewed X chromosome inactivation in X-linked mental retardation using a mouse model. Am J Hum Genet 80:1138-49 Anthony Argentaro, Ji-Chun Yang, Lynda Chapman, Monica Kowalczyk, Richard Gibbons, Douglas Higgs, David Neuhaus and Daniela Rhodes (2007) Structural Consequences of Disease-Causing Mutations in the ADD domain of the Chromatin Associated Protein ATRX. PNAS 104:11939-44 MJ Law, KM Lower, HPJ Voon, JR Hughes, D Garrick, V Viprakasit, M Mitson, M De Gobbi, M Marra, A Morris, A Abbott, SP Wilder, S Taylor, GM Santos, J Cross, H Ayyub, S Jones, J Ragoussis, D Rhodes, I Dunham, DR. Higgs & RJ Gibbons (2010) ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size dependent manner Cell 143:367-78

Markers of Esteem 1980 Martin Wronker Award, University of Oxford 1980 Theodore Williams Scholarship in Pathology, University of Oxford 1981 Domus Scholarship, Linacre College, Oxford 1983 Hobson Memorial Scholarship, University of Oxford 2000 Fellow of the Royal College of Physicians 2007 Fellow of the Academy of Medical Sciences 2007 Local Clinical Excellence Award 2010 Conferment of title Professor of Clinical Genetics

Current Grant Support MRC Daphne Jackson Foundation (Caroline Scott) Commonwealth Scholarship (Sachith Mettananda)