WIMM PI
Curriculum Vitae
Personal Data
Name Veronica Jennifer BUCKLE
Nationality UK
Present Position
1994-present Group Leader in MRC Molecular Haematology Unit (WIMM)
Core theme – Nuclear Organisation and Erythropoiesis.
Previous Positions
1987 - 94 Research Scientist, MRC Molecular Haematology Unit, NDM and WIMM.
Human genome mapping and leukaemia genetics
1985 - 87 Post-doctoral research, Genetics Laboratory, Oxford University.
Mapping of human disease using in situ hybridisation
1982 - 85 D. Phil. Joe Patrick Fellowship from Muscular Dystrophy Group of Great Britain, Genetics Laboratory and Wolfson College, Oxford University.
Genetic analysis of the human X chromosome
1980 - 82 Leukaemia Cytogeneticist, Dept Haematology, John Radcliffe Hospital and Dept Medical Genetics, Churchill Hospital.
1976 - 80 Research Assistant to Prof Sylvia Lawler, Institute of Cancer Research, London.
Cancer cytogenetics
1974 - 76 Research Assistant to Dr Niels Atkin. Mount Vernon Hospital, London.
Cancer cytogenetics
Research Achievements
My research has focused over the past 35 years on chromosome organisation and how disruption of that organisation relates to human disease. My early work on cancer cytogenetics identified novel non-random chromosome abnormalities together with their prognostic implications, and helped unravel the genetic basis of complete and partial hydatidiform moles. My thesis work in the Genetics Laboratory Oxford achieved improved mapping for several human disease genes, including Duchenne muscular dystrophy, haemophilia B and cystic fibrosis, and led to collaborative work on XY homology and telomere structure. Moving to the Molecular Haematology Unit, my work has continued on genetic analysis of human disease, including leukaemia, alpha thalassaemia with mental retardation (ATR16), congenital dyserythropoietic anaemia (CDA1), but is principally now concentrated on chromatin organisation and the regulation of globin gene expression. Understanding fundamental aspects of gene regulation can provide insights into disease processes. My group has found, within a model of erythroid differentiation, that the tendency of genes to associate within the nucleus, which varies between different genes, is directly dependent on the surrounding chromatin environment. We find that spatial associations are a frequent occurrence between some active genes but that this is not due to shared transcription factories and is not a functional necessity for transcription. We proposed that active genes, particularly those on stretches of decondensed chromatin, can be brought into close proximity on a probabilistic basis by the nucleation of multiple splicing associated proteins and small nuclear ribonucleoproteins into nuclear speckles. Our findings contribute to the growing body of evidence that the central processes of transcription, replication and repair are all self-organised within the nucleus. We are now focusing on the physical organisation of chromatin across the alpha globin gene regulatory region during erythroid differentiation to determine the chromatin conformations required for active transcription.
Future Aims
The alpha globin gene region is one of the best-characterised segments of the genome and it is an ideal model with which to investigate how chromatin domains are established and altered during the course of development and differentiation. Analysis of single cells will be an essential complement to the genome-wide studies of chromatin configurations undertaken within the Unit. We plan to look in detail at the kinetics of transcription and at spatial relationships within the alpha globin regulatory region in live cells, using super-resolution microscopy. We will ask what part chromatin looping, involving enhancers and promoters, Polycomb-bound sites and boundary elements, and chromatin condensation contribute to gene regulation. Close collaboration with the Higgs group gives us access to a range of potentially informative knockouts whilst we can characterise nascent transcription in the various erythroid models. The organisation of transcription sites within the nucleus requires further clarity and the arrival of STED imaging in the WIMM will allow us the look in fine detail at the positioning of the globin genes with respect to RNA polymerase II and other critical nuclear proteins.
In addition to these fundamental aspects of gene regulation we continue to characterise disorders of red blood cells. Having identified a second gene underlying congenital dyserythropoietic anaemia type 1 (CDA1) we are undertaking functional studies to investigate the role that the two CDA1 genes, CDAN1 and c15orf41, play in normal erythropoiesis, and why mutations in either of these genes cause such devastating disruption to chromatin structure in erythroblasts.
The aims of my programme have been planned to integrate closely with the work of the Higgs group to ensure a smooth transition on my retirement. To further that end my postdoc Chris Babbs is also taking forward several projects, looking at unexplained anaemias, unexpectedly severe thalassaemia, unlinked beta thalassaemia, surviving fetal hydrops and zeta globin regulation, with the ultimate aim of restoring balanced globin expression in thalassaemia patients.
How do These Aims Contribute to the Understanding and/or Management of Human Disease
The breadth of my research programme uses both basic science and more clinically-orientated projects to gain an understanding of human erythropoietic diseases. By establishing principles governing successful transcription from the alpha globin genes we hope to contribute to an understanding of how normal transcription may be restored in disease. Conversely human erythroid disorders can shed light on the normal processes required for transcription. We are unpicking the genetic abnormalities associated with ATR16 syndrome, investigating the cause of erythroid abnormalities found in CDA1 and the basis of a range of haemoglobinopathies. At a clinical level our findings have already been very useful in family studies and genetic counselling.
Lay Summary of Research
Now that the human genome has been sequenced, the challenge for scientists is to understand the normal functions of our genes and how those become disrupted in disease. Such work may then allow us to develop novel therapies to counteract the effects of the disregulation underlying genetic disease. We are concentrating on how the alpha globin genes are normally switched on to produce globin protein during the development of red blood cells. We want to see how specific regions of DNA are organised in a cell nucleus and what may disrupt that organisation to affect protein production. We are also looking at other genes than can have defects causing anaemias and thalassaemias. In addition to giving us an understanding of how red blood cells develop, this work can be very useful for individual families needing genetic counselling.
All Publications Over the Past 5 Years
Brown JM, Green J, das Neves RP, Wallace HA, Smith AJH, Hughes J, Gray N, Taylor S, Wood WG, Higgs DR, Iborra FJ & Buckle VJ (2008) Association between active genes occurs at nuclear speckles and is modulated by chromatin environment. J Cell Biol, 182, 1083-1097.
Hong D, Gupta R, Ancliff P, Atzberger A, Brown J, Soneji S, Green J, Colman S, Piacibello W, Buckle V, Tsuzuki S, Greaves M & Enver T (2008) Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science, 319, 336-339.
Iborra FJ & Buckle V (2008) Wide confocal cytometry: a new approach to study proteomic and structural changes in the cell nucleus during the cell cycle. Histochem Cell Biol, 129, 45-53.
Brown JM & Buckle VJ (2010) Detection of nascent RNA transcripts by fluorescence in situ hybridization. Methods Mol Biol, 659, 33-50.
Merryweather-Clarke AT, Atzberger A, Soneji S, Gray N, Clark K, Waugh C, McGowan SJ, Taylor S, Nandi AK, Wood WG, Roberts DJ, Higgs DR, Buckle VJ & Robson KJH (2011) Global gene expression analysis of human erythroid progenitors. Blood, 117, e96-e108.
Renella R, Roberts NA, Brown JM, De Gobbi M, Bird LE, Hassanali T, Sharpe JA, Sloane-Stanley J, Ferguson DJP, Cordell J, Buckle VJ, Higgs DR & Wood WG (2011) Codanin-1 mutations in congenital dyserythropoietic anemia type 1 affect HP1alpha localization in erythroblasts. Blood, 117, 6928-6938.
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.
Lutz C, Woll PS, Hall G, Castor A, Dreau H, Cazzaniga G, Zuna J, Jensen C, Clark SA, Biondi A, Mitchell C, Ferry H, Schuh A, Buckle V, Jacobsen SE & Enver T (2012) Quiescent leukaemic cells account for minimal residual disease in childhood lymphoblastic leukaemia. Leukemia, Oct 22. doi: 10.1038/leu.2012.1306.
Schodel J, Bardella C, Sciesielski LK, Brown JM, Pugh CW, Buckle V, Tomlinson IP, Ratcliffe PJ & Mole DR (2012) Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression. Nature genetics, 44, 420-425, S421-422.
Canals AZ, Neves R, Reittie J, Iniguez C, Soneji S, Enver T, Buckle V & Iborra FJ (2012) A biophysical model for transcription factories. BMC Biophysics, Feb 9;6:2.
Babbs C, Roberts NA, Sanchez-Pulido L, McGowan SJ, Ahmed MR, Brown JM, Sabry MA, Bentley DR, McVean GA, Donnelly P, Gileadi O, Ponting CP, Higgs DR & Buckle VJ (2013) Homozygous mutations in a predicted endonuclease cause Congenital Erythropoietic Anaemia Type I. Haematologica, Sep;98(9):1383-7.
Ten Key Publications Throughout your Career
Atkin NB & Pickthall VJ (1977) Chromosomes 1 in 14 ovarian cancers. Heterochromatin variants and structural changes. Human genetics, 38, 25-33. (135 citations)
Sieff CA, Chessells JM, Harvey BA, Pickthall VJ & Lawler SD (1981) Monosomy 7 in childhood: a myeloproliferative disorder. British journal of haematology, 49, 235-249. (122 citations)
Lawler SD, Fisher RA, Pickthall VJ, Povey S & Evans MW (1982) Genetic studies on hydatidiform moles. I. The origin of partial moles. Cancer genetics and cytogenetics, 5, 309-320. (137 citations) and Lawler SD, Povey S, Fisher RA & Pickthall VJ (1982) Genetic studies on hydatidiform moles. II. The origin of complete moles. Annals of human genetics, 46, 209-222. (90 citations)
Moir DJ, Jones PA, Pearson J, Duncan JR, Cook P & Buckle VJ (1984) A new translocation, t(1;3) (p36;q21), in myelodysplastic disorders. Blood, 64, 553-555. (63 citations)
Buckle V, Mondello C, Darling S, Craig IW & Goodfellow PN (1985) Homologous expressed genes in the human sex chromosome pairing region. Nature, 317, 739-741. (60 citations)
Boyd Y & Buckle VJ (1986) Cytogenetic heterogeneity of translocations associated with Duchenne muscular dystrophy. Clinical genetics, 29, 108-115. (73 citations)
Searle AG, Peters J, Lyon MF, Hall JG, Evans EP, Edwards JH & Buckle VJ (1989) Chromosome maps of man and mouse. IV. Annals of human genetics, 53, 89-140. (209 citations)
Brown WR, MacKinnon PJ, Villasante A, Spurr N, Buckle VJ & Dobson MJ (1990) Structure and polymorphism of human telomere-associated DNA. Cell, 63, 119-132. (295 citations)
Barnett MA, Buckle VJ, Evans EP, Porter AC, Rout D, Smith AG & Brown WR (1993) Telomere directed fragmentation of mammalian chromosomes. Nucleic acids research, 21, 27-36. (126 citations)
Levy ER, Parganas E, Morishita K, Fichelson S, James L, Oscier D, Gisselbrecht S, Ihle JN & Buckle VJ (1994) DNA rearrangements proximal to the EVI1 locus associated with the 3q21q26 syndrome. Blood, 83, 1348-1354. (75 citations)
Flint J, Wilkie AO, Buckle VJ, Winter RM, Holland AJ & McDermid HE (1995) The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nature genetics, 9, 132-140. (390 citations)
Azuara V, Brown KE, Williams RR, Webb N, Dillon N, Festenstein R, Buckle V, Merkenschlager M & Fisher AG (2003) Heritable gene silencing in lymphocytes delays chromatid resolution without affecting the timing of DNA replication. Nature cell biology, 5, 668-674. (79 citations)
Brown JM, Leach J, Reittie JE, Atzberger A, Lee-Prudhoe J, Wood WG, Higgs DR, Iborra FJ & Buckle VJ (2006) Coregulated human globin genes are frequently in spatial proximity when active. The Journal of Cell Biology, 172, 177-187. (124 citations)
Brown JM, Green J, das Neves RP, Wallace HA, Smith AJ, Hughes J, Gray N, Taylor S, Wood WG, Higgs DR, Iborra FJ & Buckle VJ (2008) Association between active genes occurs at nuclear speckles and is modulated by chromatin environment. The Journal of Cell Biology, 182, 1083-1097. (98 citations)
Schodel J, Bardella C, Sciesielski LK, Brown JM, Pugh CW, Buckle V, Tomlinson IP, Ratcliffe PJ & Mole DR (2012) Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression. Nature genetics, 44, 420-425. (22 citations)
Current Grant Support
MRC Unit Award 2012-2017
Committees and Advisory Boards
Micron Oxford bio-imaging group
WIMM Imaging Committee
Editorial Boards
Assistant Editor for Human Molecular Genetics
Ad Hoc reviewer for:
Many journals including J Cell Biol, J Cell Science, PLOS, Genome Biology, Experimental Cell Research, Trends in Genetics, Chromosome Research, Chromosoma
Grant reviewer for:
Wellcome Trust, BBSRC, Leukaemia and Lymphoma Research, MRC