Dr Rui Monteiro

Dr Rui Monteiro

Institute of Cancer and Genomic Sciences
Birmingham Fellow

Contact details

Address
IBR West
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT

The Monteiro Lab studies the fundamental mechanisms underpinning haematopoiesis in development and homeostasis and how perturbations in these mechanisms lead to haematopoietic disease.

What factors direct cells of a particular lineage(endothelium) to de-differentiate and become a stem cell for a different tissue type (blood)? How do these stem cells maintain the balance between differentiation and self-renewal and what happens when that fails? 

Haematopoietic stem cells (HSCs) arise during embryonic development and generate and maintain all the blood lineages throughout adult life. They arise from the haemogenic endothelium (HE), a specialized subset of endothelial cells located in the floor of the main embryonic artery, the dorsal aorta. Importantly, HSC ontogeny is conserved throughout vertebrate development, allowing the use of animal models like the zebrafish to gain fundamental insights into the molecular mechanisms that shape this process. We use a broad range of techniques like transgenesis and gene editing, genome-wide analysis of chromatin accessibility and epigenetic marks and single-cell transcriptional profiling.

The goal is to understand how extrinsic factors, transcriptional regulators and cis-regulatory regions (enhancers) interplay to carry out key lineage decisions that enable the emergence of HSCs and their self-renewal and differentiation to give rise to all haematopoietic lineages (e.g. erythrocytes, macrophages, T-cells). Understanding of how these factors interact to generate and maintain a healthy haematopoietic system in a whole organism is critical both to design new approaches to generating stem cells in vitro but also to help design effective interventions when haematopoiesis is perturbed in diseases such as leukaemias.

Qualifications

  • PhD in Developmental Biology, Hubrecht Institute, University of Utrecht, The Netherlands (2005)
  • MSc (equivalent 5-year degree) in Biochemistry, University of Lisbon, Portugal (2000)

Biography

Rui started his research career as an undergraduate, studying Notch target genes in chick embryos at the Instituto de Histologia e Embriologia, University of Lisbon, Portugal. After graduating in 2000, he went on to pursue a PhD in Developmental Biology at the Hubrecht Institute, University of Utrecht, The Netherlands. He graduated in 2005, and during this period studied BMP signalling in mouse and in zebrafish. In 2006 he joined Prof Patient’s lab at the Weatherall Institute of Molecular Medicine, University of Oxford to do research on developmental haematopoiesis. In 2014, he was awarded a BHF Intermediate Basic Science Research Fellowship and became a Principal Investigator at the Radcliffe Department of Medicine, University of Oxford. He became a University Research Lecturer in 2016. Rui joined the University of Birmingham in 2018 as a Birmingham Fellow.

Postgraduate supervision

Rui has supervised three undergraduate and three PhD students and is interested in supervising doctoral research in the following areas:

  • The role of transcriptional and epigenetic regulators in endothelial and haematopoietic development
  • High throughput screening of endothelial and haemogenic-specific cis-regulatory elements in zebrafish
  • In vivo modelling of the genetic basis of human disease in zebrafish

If you are interested in studying any of these subject areas please contact Rui on the contact details above.

Research

Zebrafish has become an important resource for biomedical research, helping to understand human disease and addressing critical questions in regenerative medicine. Because zebrafish share the same genes with other vertebrates, including humans, and angiogenesis and haematopoiesis are so well conserved, the lessons we learn from this model can be directly applied to other vertebrate systems and to human health. The Monteiro Lab are interested in learning how extrinsic signalling and intrinsic transcriptional regulators control lineage fate decisions and thus programme the embryonic endothelium towards a blood stem cell (HSC) fate. To this end, they use a mix of classical developmental biology approaches with novel cutting edge approaches like genome editing with CRISPR/Cas9, transcriptional and epigenetic profiling and screening by transient transgenesis. Their current research interests are: 

  1. The role of TGFb signalling in the formation of HSCs and how that relates to its function in making blood vessels. Gaining insights into the role of TGFβ in vascular and blood stem cell biology in vivo is particularly relevant, given that the TGFβ pathway is an attractive therapeutic target in haematopoietic malignancies and cardiovascular disease.
  2. To develop in vivo leukaemia models in zebrafish. Transcriptional regulators that are important for HSC formation in the embryo are frequently mutated or mis-expressed in haematopoietic malignancies. Here, Rui’s group is developing a zebrafish model for gata2 haploinsufficiency syndromes such as Emberger’s or MonoMAC syndrome, for which there are no curative therapies beyond allogeneic stem cell transplants.
  3. Cis-regulatory elements that drive cell fate specification in endothelium and in blood stem cells. We are interesting in identifying key tissue-specific enhancers that drive gene expression during the haematopoietic process. Profiling their activity in vivo will help to dissect the tissue-specific functions of particular transcription factors and how it impinges in the development of the embryonic cardiovascular and haematopoietic systems. 

Postdoctoral researchers:

Other activities

  • Member of the British Society of Developmental Biology
  • Member of the Biochemical Society
  • Member of the EuFishBioMed Society
  • Member of the Zebrafish Disease Models Society 
  • Reviewer for scientific journals, including Nature, Developmental Cell, Cell Stem Cell, Cell Reports, Stem Cell Reports, PLoS journals, Development, Advances in Haematology, Haematologica, Blood and EMBO Journal. Rui also reviews national grant proposals (MRC, BBSRC, KKLF). 
  • Member of the Radcliffe Department of Medicine Sponsored Nursery Places Panel. 2015-2017
  • Member of the Clinical Medicine Animal Welfare and Ethical Review Body (University of Oxford) 2007-2017

Publications

Recent publications

Article

Dobrzycki, T, Mahony, CB, Krecsmarik, M, Koyunlar, C, Rispoli, R, Peulen-Zink, J, Gussinklo, K, Fedlaoui, B, de Pater, E, Patient, R & Monteiro, R 2020, 'Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult zebrafish haematopoiesis', Communications Biology, vol. 3, no. 1, 71. https://doi.org/10.1038/s42003-020-0798-3

Dobrzycki, T, Krecsmarik, M & Monteiro, R 2020, 'Genotyping and Quantification of In Situ Hybridization Staining in Zebrafish', Journal of Visualized Experiments , no. 155, e59956. https://doi.org/10.3791/59956

Dobrzycki, T, Lalwani, M, Telfer, C, Monteiro, R & Patient, R 2020, 'The roles and controls of GATA factors in blood and cardiac development', IUBMB Life, vol. 72, no. 1, pp. 39-44. https://doi.org/10.1002/iub.2178

Bonkhofer, F, Rispoli, R, Pinheiro, P, Krecsmarik, M, Schneider-Swales, J, Tsang, IHC, Bruijn, MD, Monteiro, R, Peterkin, T & Patient, R 2019, 'Blood stem cell-forming haemogenic endothelium in zebrafish derives from arterial endothelium', Nature Communications. https://doi.org/10.1038/s41467-019-11423-2

Bonkhofer, F, Rispoli, R, Pinheiro, P, Krecsmarik, M, Schneider-Swales, J, Tsang, IHC, de Bruijn, M, Monteiro, R, Peterkin, T & Patient, R 2019, 'Blood stem cell-forming haemogenic endothelium in zebrafish derives from arterial endothelium', Nature Communications, vol. 10, no. 1, 3577. https://doi.org/10.1038/s41467-019-11423-2

Dobrzycki, T, Krecsmarik, M, Bonkhofer, F, Patient, R & Monteiro, R 2018, 'An optimized pipeline for parallel image-based quantification of gene expression and genotyping after in situ hybridization', Biology Open, pp. bio.031096. https://doi.org/10.1242/bio.031096

Lopes, SS, Distel, M, Linker, C, Fior, R, Monteiro, R, Bianco, IH, Portugues, R, Strähle, U & Saúde, L 2016, 'Report of the 4th European Zebrafish principal investigator meeting', Zebrafish, vol. 13, no. 6, pp. 590-595. https://doi.org/10.1089/zeb.2016.1364

Monteiro, R, Pinheiro, P, Joseph, N, Peterkin, T, Koth, J, Repapi, E, Bonkhofer, F, Kirmizitas, A & Patient, R 2016, 'Transforming Growth Factor β Drives Hemogenic Endothelium Programming and the Transition to Hematopoietic Stem Cells', Developmental Cell, vol. 38, no. 4, pp. 358-370. https://doi.org/10.1016/j.devcel.2016.06.024

Crisan, M, Solaimani Kartalaei, P, Neagu, A, Karkanpouna, S, Yamada-Inagawa, T, Purini, C, Vink, CS, Van Der Linden, R, Van Ijcken, W, Chuva De Sousa Lopes, SM, Monteiro, R, Mummery, C & Dzierzak, E 2016, 'BMP and Hedgehog Regulate Distinct AGM Hematopoietic Stem Cells Ex Vivo', Stem Cell Reports, vol. 6, no. 3, pp. 383-395. https://doi.org/10.1016/j.stemcr.2016.01.016

Crisan, M, Kartalaei, PS, Vink, C, Yamada-Inagawa, T, Bollerot, K, Van Ijcken, W, Van Der Linden, R, De Sousa Lopes, SMC, Monteiro, R, Mummery, C & Dzierzak, E 2015, 'BMP signalling differentially regulates distinct haematopoietic stem cell types', Nature Communications, vol. 6, 8040. https://doi.org/10.1038/ncomms9040

Gu, W, Monteiro, R, Zuo, J, Simões, FC, Martella, A, Andrieu-Soler, C, Grosveld, F, Sauka-Spengler, T & Patient, R 2015, 'A Novel TGFβ Modulator that Uncouples R-Smad/I-Smad-Mediated Negative Feedback from R-Smad/Ligand-Driven Positive Feedback', PLoS Biology, vol. 13, no. 2, e1002051. https://doi.org/10.1371/journal.pbio.1002051

Gorsi, B, Liu, F, Ma, X, Chico, TJA, Shrinivasan, A, Kramer, KL, Bridges, E, Monteiro, R, Harris, AL, Patient, R & Stringer, SE 2014, 'The heparan sulfate editing enzyme Sulf1 plays a novel role in zebrafish VegfA mediated arterial venous identity', Angiogenesis, vol. 17, no. 1, pp. 77-91. https://doi.org/10.1007/s10456-013-9379-0

Comment/debate

Crisan, M, Kartalaei, PS, Vink, CS, Yamada-Inagawa, T, Bollerot, K, Van Ijcken, W, Van Der Linden, R, De Sousa Lopes, SMC, Monteiro, R, Mummery, C & Dzierzak, E 2015, 'Erratum: BMP signalling differentially regulates distinct haematopoietic stem cell types(Nature Communications (2015) 6 (8040))', Nature Communications, vol. 6, 8793. https://doi.org/10.1038/ncomms9793

Review article

Ciau-Uitz, A, Monteiro, R, Kirmizitas, A & Patient, R 2014, 'Developmental hematopoiesis: Ontogeny, genetic programming and conservation', Experimental Hematology, vol. 42, no. 8, pp. 669-683. https://doi.org/10.1016/j.exphem.2014.06.001

Working paper

Dobrzycki, T, Krecsmarik, M, Koyunlar, C, Rispoli, R, Peulen-Zink, J, Gussinklo, K, Pater, ED, Patient, R & Monteiro, R 2019 'A zebrafish model for MonoMAC syndrome identifies an earlier role for gata2 in haemogenic endothelium programming and generation of haematopoietic stem cells' bioRxiv, pp. 1-38. https://doi.org/10.1101/516203

View all publications in research portal