Genome Structure and Regulation
Our research into gene regulation and epigenetics interfaces with cancer cell and stem cell biology, viral oncology (EBV and HPV), development and genome biology. We use both functional genomics and high throughput methods to determine how genetic abnormalities unravel the complex regulatory networks that underlie cancer and normal development. In parallel we are studying the gene regulatory mechanisms that control the normal development and differentiation of stem cells.
Research Theme Lead and Deputy Lead
Professor Ferenc Mueller
Professor in Developmental Genetics / Research Theme Lead
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Dr Rui Monteiro
Associate Professor / Research Theme Deputy Lead
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Research groups
Spotlight on marrow failure in a zebrafish model of GATA2 deficiency
The Monteiro group employed a zebrafish fish model to replicate what happens in patients who inherit the loss of one allele of the GATA2 gene who develop bone marrow failure and leukaemia. Zebrafish lacking a transcriptional enhancer needed for efficient GATA2 expression exhibit a gradual loss of myeloid blood cells, a skewing towards red blood cells, and an AML-like syndrome.
Cell Reports 42:112571 (2023). Christopher B Mahony, Lucy Copper, Pavle Vrljicak, Boris Noyvert, Chrystala Constantinidou, Sofia Browne, Yi Pan, Claire Palles, Sascha Ott, Martin R Higgs, Rui Monteiro. . doi: https://doi.org/10.1016/j.celrep.2023.112571
GATA2 deficiency is a rare genetic bone marrow disorder in which patients are at increased risk of blood cancers. This is likely due to (i) GATA2-deficient blood stem cells in bone marrow producing significantly fewer immune cells used to fight infection, and (ii) the GATA2 gene mutation resulting in impaired activity of genes that are involved in repairing ongoing damage to their DNA.
In humans, GATA2 haploinsufficiency due to mutations in coding or enhancer regions causes hematopoietic disorders collectively referred to as GATA2 deficiency syndromes. 75% of patients with inherited germline GATA2 mutations develop early-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
In the zebrafish model employed here, both alleles of an enhancer controlling the gata2a locus were deleted. This generated a bona fide model of GATA2 deficiency that shows marrow hypocellularity, neutropenia, increased susceptibility to infections, and development of an AML-like phenotype in the adult kidney marrow.
Spotlight on global analysis of enhancers that control blood cell development
New study uncovers the information encoded in our DNA required for the transcriptional control of blood cell development from embryonic stem cells
This publication from the Bonifer laboratory describes a novel genome-wide screen that identified and functionally characterised distinct subsets of gene regulatory elements that direct the different stages of the development of blood cells from embryonic stem cells (ESC)
Nature Communications 14:267 (2023). Edginton-White B, A Maytum, SG Kellaway, DK Goode, P Keane,. . . C Bonifer. A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification.
This study of the genome investigated the functions of all of the regulatory elements within our DNA that are required to express our genes in the right cells, at the right levels, and at the right time. These regulatory elements are called enhancers and are scattered over large distances within the the 3 billion bases of DNA that make up the genome. Enhancers also function to integrate multiple highly specific intrinsic and extrinsic signals, whereby most regulatory elements only function in a subset of cells. The Bonifer laboratory developed a whole genome assay able to define the precise time course of activation of enhancers, and their responses to external signals, during the stepwise development of blood cells from ESCs. These analyses identified thousands of differentially active enhancers able to stimulate a promoter across different stages of blood cell development from ESCs. It also showed that blood cell-specific gene expression is controlled by the concerted action of thousands of differentiation stage-specific sets of enhancers and promoters, many of which respond to the cytokine signals promoting cell differentiation towards blood cells. This work highlights the mechanisms of how and where extrinsic signals program a cell type-specific regulatory landscape driving hematopoietic differentiation.
This methodology, which can now be adapted to any ESC-derived cell type, also provides a way to investigate how gene expression is sometimes perturbed by mutations in enhancers or external signals which cause disease. To understand how genes respond to outside signals and are deregulated in disease, we need to know where these enhancer elements are, when they are active and how they function.
Spotlight on Cancer Genomics
Nature Genetics 51:151-162 (2019). Assi SA, MR Imperato, DJL Coleman, A Pickin, S Potluri, A Ptasinska, . . . PN Cockerill, C Bonifer. Subtype-specific regulatory network rewiring in acute myeloid leukemia.
A study by Constanze Bonifer and Peter Cockerill has revealed the roles that different types of gene mutations play in causing acute myeloid leukaemia. Epigenetic profiling of regulatory elements revealed that mutation-specific subsets of AML have distinct patterns of gene expression. Each subset was controlled by distinct gene regulatory networks linked to mutations in transcription factors and signalling molecules This research brings us one step closer to being able to provide tailored and targeted treatment specific to individual patients, increasing their chances of survival.
Selected Highlights from Gene Structure and Regulation
Cell Reports 42:112571 (2023). Christopher B Mahony, Lucy Copper, Pavle Vrljicak, Boris Noyvert, Chrystala Constantinidou, Sofia Browne, Yi Pan, Claire Palles, Sascha Ott, Martin R Higgs, Rui Monteiro. . doi: https://doi.org/10.1016/j.celrep.2023.112571
Blood 2022019138 (2023). Clarke ML, RB Lemma, DS Walton, G Volpe, B Noyvert, OS Gabrielsen and J Frampton. . doi: 10.1182/blood.2022019138
Nature Commun 14:267 (2023). Edginton-White B, A Maytum, SG Kellaway, DK Goode, P Keane,. . . C Bonifer. .
Dev Cell 58:155-170 e158 (2023). Hadzhiev Y, L Wheatley, L Cooper, F Ansaloni, C Whalley, Z Chen, . . . A Beggs, F Muller. .
Blood doi: 10.1182/blood.2021015036 (2022). Tirtakusuma R, K Szoltysek, P Milne, V Grinev, A Ptasinska, PS Chin, . . . C Bonifer, O Heidenreich, S Bomken. .
Elife 11 (2022). Vilaplana-Lopera N, V Cuminetti, R Almaghrabi, G Papatzikas, AK Rout, M Jeeves, . . . P Garcia. .
Nat Genet 54:1037-1050 (2022). Baranasic D, M Hortenhuber, PJ Balwierz, T Zehnder, AK Mukarram, C Nepal, . . . F Muller. .
Cancer Lett 501:172-186 (2021). Gleneadie HJ, AH Baker, N Batis, J Bryant, Y Jiang, SJH Clokie, H Mehanna, P Garcia, DMA Gendoo. . . JL Parish, FL Khanim, M Wiench.
Front Immunol 12:642807 (2021). Bevington SL, R Fiancette, DW Gajdasik, P Keane, JK Soley, CM Willis, . . . PN Cockerill. .
Life Science Alliance 4 (2021). Kellaway SG, P Keane, B Edginton-White, K Regha, E Kennett and C Bonifer. .
Cell Reports 34:108759 (2021). Wang J, P Rojas, J Mao, M Muste Sadurni, O Garnier, S Xiao, . . . MR Higgs, P Garcia, M Saponaro. .
Frontiers in Immunology 12:642807 (2021). Bevington SL, R Fiancette, DW Gajdasik, P Keane, JK Soley, CM Willis, . . . PN Cockerill. Stable .
EMBO Reports 22:e51120 (2021). Blakemore D, N Vilaplana-Lopera, R Almaghrabi, E Gonzalez, M Moya, C Ward, . .A Gambus, E Petermann, GS Stewart, P Garcia. .
Scientific Reports 11:3009 (2021). Halsall JA, S Andrews, F Krueger, CE Rutledge, G Ficz, W Reik and BM Turner. .
Cell Reports 35:109010 (2021). Potluri S, SA Assi, PS Chin, DJL Coleman, A Pickin, S Moriya, . . . PN Cockerill, C Bonifer. .
J General Virology 101:873-883 (2020). Hollingworth R, GS Stewart and RJ Grand. .
EMBO J:e105220 (2020). Bevington SL, P Keane, JK Soley, S Tauch, DW Gajdasik, R Fiancette, . . . PN Cockerill. . doi: 10.15252/embj.2020105220
Cell Rep 31:107748 (2020). Bevington SL, STH Ng, GJ Britton, P Keane, DC Wraith and PN Cockerill. .
Commun Biol 3:71 (2020). Dobrzycki T, CB Mahony, M Krecsmarik, C Koyunlar, R Rispoli, J Peulen-Zink, . . . R Monteiro. .
Haematologica (2020). Kellaway SG, P Keane, E Kennett and C Bonifer. . DOI: 10.3324/haematol.2019.241885
Life Sci Alliance 3 (2020). Kwon SY, K Massey, MA Watson, T Hussain, G Volpe, CD Buckley, . . . P Badenhorst. .
Cell Rep 31:107691 (2020). Nafria M, P Keane, ES Ng, EG Stanley, AG Elefanty and C Bonifer. .
Nucleic Acids Res 48:8374-8392 (2020). Wragg JW, L Roos, D Vucenovic, N Cvetesic, B Lenhard and F Muller. .
J Virol 10.1128 (2020). Molloy DP and RJ Grand. S.
Nat Genet 51:151-162 (2019). Assi SA, MR Imperato, DJL Coleman, A Pickin, S Potluri, A Ptasinska, . . . PN Cockerill, C Bonifer. .
Nat Commun 10:3577 (2019). Bonkhofer F, R Rispoli, P Pinheiro, M Krecsmarik, J Schneider-Swales, IHC Tsang, . . . R Monteiro, T Peterkin, R Patient. .
Nat Commun 10:691 (2019). Hadzhiev Y, HK Qureshi, L Wheatley, L Cooper, A Jasiulewicz, H Van Nguyen, . . . F Muller. .
Cell Rep 28:3022-3031 e3027 (2019). Ptasinska A, A Pickin, SA Assi, PS Chin, L Ames, R Avellino, . . . C Bonifer. .
Cancer Cell 34:674-689 e678 (2018). de Boer B, J Prick, MG Pruis, P Keane, MR Imperato, J Jaques, . . . C Bonifer, JJ Schuringa..
Cancer Cell 34:626-642 e628 (2018). Martinez-Soria N, L McKenzie, J Draper, A Ptasinska, H Issa, S Potluri, . . . C Bonifer, O Heidenreich. .
Cell Rep 24:1496-1511 e1498 (2018). Ward C, G Volpe, P Cauchy, A Ptasinska, R Almaghrabi, D Blakemore, . . . P Garcia. .
J Immunol 199:2652-2667 (2017). Brignall R, P Cauchy, SL Bevington, B Gorman, AO Pisco, J Bagnall, . . . P Cockerill, P Paszek. .
J Virol 91 (2017). Harris L, L McFarlane-Majeed, K Campos-Leon, S Roberts and JL Parish. .
Cell Rep 19:1654-1668 (2017). Loke J, SA Assi, MR Imperato, A Ptasinska, P Cauchy, Y Grabovska, . . . C Bonifer. .
Nucleic Acids Res 45:9874-9888 (2017). Stanulovic VS, P Cauchy, SA Assi and M Hoogenkamp. .
Sci Rep 7:11148 (2017). Volpe G, DS Walton, DE Grainger, C Ward, P Cauchy, D Blakemore, . . . J Frampton. .
EMBO J 35:515-535 (2016). Bevington SL, P Cauchy, J Piper, E Bertrand, N Lalli, RC Jarvis, . . . PN Cockerill. .
PLoS Genet 12:e1005969 (2016). Kwon SY, V Grisan, B Jang, J Herbert and P Badenhorst..
Epigenetics Chromatin 9:52 (2016). Wiersma M, M Bussiere, JA Halsall, N Turan, R Slany, BM Turner and KP Nightingale. .
Leukemia 10:1038 (2016). Clarke M, G Volpe, L Sheriff, D Walton, C Ward, W Wei, . . . J Frampton. .
Dev Cell 36:572-587 (2016). Goode DK, N Obier, MS Vijayabaskar, ALM Lie, AJ Lilly, R Hannah, . . . C Bonifer. .
Dev Cell 38:358-370 (2016). Monteiro R, P Pinheiro, N Joseph, T Peterkin, J Koth, E Repapi, . . . R Patient. .
Cell Rep 12:821-836 (2015). Cauchy P, SR James, J Zacarias-Cabeza, A Ptasinska, MR Imperato, SA Assi, . . . PN Cockerill. .
J Virol 89:4770-4785 (2015). Paris C, I Pentland, I Groves, DC Roberts, SJ Powis, N Coleman, . . . JL Parish. .
Nat Commun 6:7203 (2015). Regha K, SA Assi, O Tsoulaki, J Gilmour, G Lacaud and C Bonifer..
Nature 507:381-385 (2014). Haberle V, N Li, Y Hadzhiev, C Plessy, C Previti, C Nepal, . . . F Muller, B Lenhard.
Cell reports 8:1974-1988 (2014). Ptasinska A, SA Assi, N Martinez-Soria, MR Imperato, J Piper, P Cauchy, . . . C Bonifer.
Development 141:715-724 (2014). Roberts JA, I Miguel-Escalada, KJ Slovik, KT Walsh, Y Hadzhiev, R Sanges, . . . F Muller. .
Leukemia 27:661-670 (2013). Clarke M, S Dumon, C Ward, R Jager, S Freeman, B Dawood, . . . J Frampton, P Garcia. .
Genome Res 23:1938-1950 (2013). Nepal C, Y Hadzhiev, C Previti, V Haberle, N Li, H Takahashi, . . . F Muller. .
Leukemia 27:1487-1496 (2013). Volpe G, DS Walton, W Del Pozzo, P Garcia, E Dasse, LP O'Neill, . . . J Frampton, S Dumon. .