Gene Structure and Regulation

 Gene regulation diagram

Our basic research covers cancer cell and stem cell biology, viral oncology (EBV and HPV) and genome biology. We use high throughput methods to determine how genetic abnormalities unravel the complex regulatory networks that underlie cancer. In parallel we are studying the molecular pathways that control the normal development and differentiation of stem cells.

Current research includes a £1.3 million grant from the MRC to test combinations of drugs that target the signalling molecule FLT3 together with the transcription factor RUNX1 in Acute Myeloid Leukaemia.

Theme Co-Leads

 

Jo Morris

Professor Jo Morris

Professor of Molecular Genetics

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Ferenc Mueller

Professor Ferenc Mueller

Professor in Developmental Genetics

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Research groups

Gene structure and regulation
ResearcherResearch Group
Paul Badenhorst Drosophila development and epigenetics
Constanze Bonifer Epigenetics and gene regulation in blood cells
Peter Cockerill Epigenetics and gene regulation in blood cells
Clare Davies Protein methylation in breast cancer
Jonathan Frampton Blood stem cells and leukaemia
Roger Grand (Honorary) Adenovirus biology and cellular transformation
Maarten Hoogenkamp Epigenetics and gene regulation in blood cells
Rui Monteiro TGFb signalling in haematopoiesis and endothelial biology
Ferenc Mueller Gene regulation and development in zebrafish
Joanna Parish HPV gene expression and replication
Andrew Turnell Adenovirus biology and cellular transformation
Bryan Turner Regulation of histone modifications

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. 

Gene structure and regulation diagram as detailed below

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 this Research Theme

EMBO J:e105220 (2020). Bevington SL, P Keane, JK Soley, S Tauch, DW Gajdasik, R Fiancette, . . . PN Cockerill. IL-2/IL-7-inducible factors pioneer the path to T cell differentiation in advance of lineage-defining factors. doi: 10.15252/embj.2020105220

Cell Rep 31:107748 (2020). Bevington SL, STH Ng, GJ Britton, P Keane, DC Wraith and PN Cockerill. Chromatin Priming Renders T Cell Tolerance-Associated Genes Sensitive to Activation below the Signaling Threshold for Immune Response Genes.

Commun Biol 3:71 (2020). Dobrzycki T, CB Mahony, M Krecsmarik, C Koyunlar, R Rispoli, J Peulen-Zink, . . . R Monteiro. Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis.

Haematologica  (2020). Kellaway SG, P Keane, E Kennett and C Bonifer. RUNX1-EVI1 disrupts lineage determination and the cell cycle by interfering with RUNX1 and EVI1 driven gene regulatory networks. 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. Oxidised metabolites of the omega-6 fatty acid linoleic acid activate dFOXO.

Cell Rep 31:107691 (2020). Nafria M, P Keane, ES Ng, EG Stanley, AG Elefanty and C Bonifer. Expression of RUNX1-ETO Rapidly Alters the Chromatin Landscape and Growth of Early Human Myeloid Precursor Cells.

Nucleic Acids Res 48:8374-8392 (2020). Wragg JW, L Roos, D Vucenovic, N Cvetesic, B Lenhard and F Muller. Embryonic tissue differentiation is characterized by transitions in cell cycle dynamic-associated core promoter regulation.

J Virol  (2020). Molloy DP and RJ Grand. Structural determinants within the adenovirus early region 1A protein spacer region necessary for tumourigenesis.

Nat Genet 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.

Nat Commun 10:3577 (2019). Bonkhofer F, R Rispoli, P Pinheiro, M Krecsmarik, J Schneider-Swales, IHC Tsang, . . . R Monteiro, T Peterkin, R Patient. Blood stem cell-forming haemogenic endothelium in zebrafish derives from arterial endothelium.

Nat Commun 10:691 (2019). Hadzhiev Y, HK Qureshi, L Wheatley, L Cooper, A Jasiulewicz, H Van Nguyen, . . . F Muller. A cell cycle-coordinated Polymerase II transcription compartment encompasses gene expression before global genome activation.

Cell Rep 28:3022-3031 e3027 (2019). Ptasinska A, A Pickin, SA Assi, PS Chin, L Ames, R Avellino, . . . C Bonifer. RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBPalpha- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction.

Cancer Cell 34:674-689 e678 (2018). de Boer B, J Prick, MG Pruis, P Keane, MR Imperato, J Jaques, . . . C Bonifer, JJ Schuringa. Prospective Isolation and Characterization of Genetically and Functionally Distinct AML Subclones.

Cancer Cell 34:626-642 e628 (2018). Martinez-Soria N, L McKenzie, J Draper, A Ptasinska, H Issa, S Potluri, . . . C Bonifer, O Heidenreich. The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation.

Cell Rep 24:1496-1511 e1498 (2018). Ward C, G Volpe, P Cauchy, A Ptasinska, R Almaghrabi, D Blakemore, . . . P Garcia. Fine-Tuning Mybl2 Is Required for Proper Mesenchymal-to-Epithelial Transition during Somatic Reprogramming.

J Immunol 199:2652-2667 (2017). Brignall R, P Cauchy, SL Bevington, B Gorman, AO Pisco, J Bagnall, . . . P Cockerill, P Paszek. Integration of Kinase and Calcium Signaling at the Level of Chromatin Underlies Inducible Gene Activation in T Cells.

J Virol 91 (2017). Harris L, L McFarlane-Majeed, K Campos-Leon, S Roberts and JL Parish. The Cellular DNA Helicase ChlR1 Regulates Chromatin and Nuclear Matrix Attachment of the Human Papillomavirus 16 E2 Protein and High-Copy-Number Viral Genome Establishment.

Cell Rep 19:1654-1668 (2017). Loke J, SA Assi, MR Imperato, A Ptasinska, P Cauchy, Y Grabovska, . . . C Bonifer. RUNX1-ETO and RUNX1-EVI1 Differentially Reprogram the Chromatin Landscape in t(8;21) and t(3;21) AML.

Nucleic Acids Res 45:9874-9888 (2017). Stanulovic VS, P Cauchy, SA Assi and M Hoogenkamp. LMO2 is required for TAL1 DNA binding activity and initiation of definitive haematopoiesis at the haemangioblast stage.

Sci Rep 7:11148 (2017). Volpe G, DS Walton, DE Grainger, C Ward, P Cauchy, D Blakemore, . . . J Frampton. Prognostic significance of high GFI1 expression in AML of normal karyotype and its association with a FLT3-ITD signature.

EMBO J 35:515-535 (2016). Bevington SL, P Cauchy, J Piper, E Bertrand, N Lalli, RC Jarvis, . . . PN Cockerill. Inducible chromatin priming is associated with the establishment of immunological memory in T cells.

PLoS Genet 12:e1005969 (2016). Kwon SY, V Grisan, B Jang, J Herbert and P Badenhorst. Genome-Wide Mapping Targets of the Metazoan Chromatin Remodeling Factor NURF Reveals Nucleosome Remodeling at Enhancers, Core Promoters and Gene Insulators.

Epigenetics Chromatin 9:52 (2016). Wiersma M, M Bussiere, JA Halsall, N Turan, R Slany, BM Turner and BM Turner, KP Nightingale. Protein kinase Msk1 physically and functionally interacts with the KMT2A/MLL1 methyltransferase complex and contributes to the regulation of multiple target genes.

Leukemia  (2016). Clarke M, G Volpe, L Sheriff, D Walton, C Ward, W Wei, . . . J Frampton. Transcriptional regulation of SPROUTY2 by MYB influences myeloid cell proliferation and stem cell properties by enhancing responsiveness to IL-3.

Dev Cell 36:572-587 (2016). Goode DK, N Obier, MS Vijayabaskar, ALM Lie, AJ Lilly, R Hannah, . . . C Bonifer. Dynamic Gene Regulatory Networks Drive Hematopoietic Specification and Differentiation.

Dev Cell 38:358-370 (2016). Monteiro R, P Pinheiro, N Joseph, T Peterkin, J Koth, E Repapi, . . . R Patient. Transforming Growth Factor beta Drives Hemogenic Endothelium Programming and the Transition to Hematopoietic Stem Cells.

Cell Rep 12:821-836 (2015). Cauchy P, SR James, J Zacarias-Cabeza, A Ptasinska, MR Imperato, SA Assi, . . . PN Cockerill. Chronic FLT3-ITD Signaling in Acute Myeloid Leukemia Is Connected to a Specific Chromatin Signature.

J Virol 89:4770-4785 (2015). Paris C, I Pentland, I Groves, DC Roberts, SJ Powis, N Coleman, . . . JL Parish. CCCTC-Binding Factor Recruitment to the Early Region of the Human Papillomavirus 18 Genome Regulates Viral Oncogene Expression.

Nat Commun 6:7203 (2015). Regha K, SA Assi, O Tsoulaki, J Gilmour, G Lacaud and C Bonifer. Developmental-stage-dependent transcriptional response to leukaemic oncogene expression.

Nature 507:381-385 (2014). Haberle V, N Li, Y Hadzhiev, C Plessy, C Previti, C Nepal, . . . F Muller, B Lenhard. Two independent transcription initiation codes overlap on vertebrate core promoters.

Cell reports 8:1974-1988 (2014). Ptasinska A, SA Assi, N Martinez-Soria, MR Imperato, J Piper, P Cauchy, . . . C Bonifer. Identification of a Dynamic Core Transcriptional Network in t(8;21) AML that Regulates Differentiation Block and Self-Renewal.

Development 141:715-724 (2014). Roberts JA, I Miguel-Escalada, KJ Slovik, KT Walsh, Y Hadzhiev, R Sanges, . . . F Muller. Targeted transgene integration overcomes variability of position effects in zebrafish.

Leukemia 27:661-670 (2013). Clarke M, S Dumon, C Ward, R Jager, S Freeman, B Dawood, . . . J Frampton, P Garcia. MYBL2 haploinsufficiency increases susceptibility to age-related haematopoietic neoplasia.

Genome Res 23:1938-1950 (2013). Nepal C, Y Hadzhiev, C Previti, V Haberle, N Li, H Takahashi, . . . F Muller. Dynamic regulation of the transcription initiation landscape at single nucleotide resolution during vertebrate embryogenesis.

Leukemia 27:1487-1496 (2013). Volpe G, DS Walton, W Del Pozzo, P Garcia, E Dasse, LP O'Neill, . . . J Frampton, S Dumon. C/EBPalpha and MYB regulate FLT3 expression in AML