The LMB Fellows scheme aims to facilitate or enhance long-term collaborations between scientists from across the world and LMB and its groups. LMB Fellowships are sponsored by a group, they are time limited and provide the Fellows with access to the LMB and its facilities, making the Fellows highly valued members of the LMB’s scientific community.
Sponsor:- Mariann Bienz, PNAC
Caroline Dean works at the John Innes Centre (Norwich) on epigenetic regulation of developmental control genes in Arabidopsis. This depends on heritable chromatin-associated complexes that are highly conserved between animals and plants such as Polycomb Repressive Complex 2 (PRC2). Her focus has been on FLC, whose expression determines the timing of flowering after cold spells (1). She has discovered several components of this epigenetic switch by genetic screens, including the VIN/VEL proteins. These proteins form punctate nuclear structures upon overexpression in plant and animal cells, similar to the Wnt signalosomes assembled by Dishevelled through dynamic head-to-tail polymerization of its DIX domain (2). Our collaboration is aimed at the biochemical and structural analysis of VIN/VEL proteins and their domains, to test whether VIN/VEL proteins polymerise, and whether this underpins PRC2 recruitment and heritable epigenetic switching.
- Whittaker, C., Dean, C. (2017)
The FLC Locus: A Platform for Discoveries in Epigenetics and Adaptation.
Annu Rev Cell Dev Biol 33: 555-575
- Schwarz-Romond, T., Fiedler, M., Shibata, N., Butler, P.J., Kikuchi, A., Higuchi, Y., Bienz, M. (2007)
The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization.
Nat Struct Mol Biol 14(6): 484-92
Sponsor:- Madeline Lancaster, Cell Biology
Wanda Kukulski is Professor of Biochemistry at the Institute of Biochemistry and Molecular Medicine at the University of Bern, Switzerland. Her group is interested in the diversity of specialised membrane architectures that drive cellular functions. At present, their aim is to understand the molecular organisation and function of organelle contact sites, and dynamic reorganisations of mitochondrial membranes. The core approach is to visualise membrane shape and topology as well as protein assemblies associated with cellular membranes by correlative microscopy and electron cryo-tomography.
With Madeline Lancaster’s group they are working on combining correlative microscopy with cerebral organoid technology. They aim to visualise molecular architectures in neuronal tissue, which will allow specific questions on organelle membranes in neurons to be addressed.
- Hoffmann, P.C., Bharat, T.A.M., Wozny, M.R., Boulanger, J., Miller, E.A., Kukulski, W. (2019)
Tricalbins Contribute to Cellular Lipid Flux and Form Curved ER-PM Contacts that Are Bridged by Rod-Shaped Structures.
Dev Cell 51(4): 488-502.e8
- Ader, N.R., Hoffmann, P.C., Ganeva, I., Borgeaud, A.C., Wang, C., Youle, R.J., Kukulski, W. (2019)
Molecular and topological reorganizations in mitochondrial architecture interplay during Bax-mediated steps of apoptosis.
- Bharat, T.A.M., Hoffmann, P.C., Kukulski, W. (2018)
Correlative Microscopy of Vitreous Sections Provides Insights into BAR-Domain Organization In Situ.
Structure 26(6): 879-886.e3
Sponsor:- Emmanuel Derivery, Cell Biology
Gillian Griffiths is a Wellcome Trust Principal Research Fellow based at the Cambridge Institute for Medical Research. Her research is focused on understanding the cell biology of cytotoxic T lymphocytes, key cells of the immune system that destroy virally infected and cancer cells. She identified a novel role for the centrosome in directing secretion of modified secretory lysosomes and has identified many of the proteins involved in this process by studying immunodeficiencies. Recent research has taken advantage on new advances in high resolution imaging to study the remarkable polarisation that these cells undergo when they encounter their targets. She is currently collaborating with Manu Derivery to use micropatterned surfaces to follow T cell polarisation and James Manton in using Light Sheet microscopy.
- Gawden-Bone, C.M., Frazer, G.L., Richard, A.C., Ma, C.Y., Strege, K., Griffiths, G.M. (2018)
PIP5 Kinases Regulate Membrane Phosphoinositide and Actin Composition for Targeted Granule Secretion by Cytotoxic Lymphocytes.
Immunity 49(3): 427-437.e4
- Richard, A.C., Lun, A.T.L., Lau, W.W.Y., Göttgens, B., Marioni, J.C., Griffiths, G.M. (2018)
T cell cytolytic capacity is independent of initial stimulation strength.
Nat Immunol 19(8): 849-858
Sponsor:- Felix Randow, PNAC
Paul Lehner is a Wellcome Trust Principal Research Fellow and Honorary Consultant in Infectious Diseases at the CITIID Institute in the Jeffrey Cheah Biomedical Centre, Cambridge. His research focuses on the use of genetic and quantitative proteomic approaches to understand how viruses interact with and manipulate their host cells. His application of forward-genetic screens discovered the Human Silencing Hub ‘HUSH’, the critical transcriptional epigenetic repressor complex for silencing both newly integrated retroviruses and mobile endogenous retrotransposons. His collaboration with Felix Randow will take advantage of their complementary expertise to gain mechanistic insights into microbial pathogenesis using genetic and proteomic discovery platforms. They anticipate the discovery of common themes by which different pathogens exploit cellular pathways to overcome cell autonomous immunity and evade cellular recognition.
- Tchasovnikarova, I.A., Timms, R.T., Douse, C.H., Roberts, R.C., Dougan, G., Kingston, R.E., Modis, Y., Lehner, P.J. (2017)
Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2.
Nat Genet 49(7): 1035-1044
- Greenwood, E.J., Matheson, N.J., Wals, K., van den Boomen, D.J., Antrobus, R., Williamson, J.C., Lehner, P.J. (2016)
Temporal proteomic analysis of HIV infection reveals remodelling of the host phosphoproteome by lentiviral Vif variants.
- Tchasovnikarova, I.A., Timms, R.T., Matheson, N.J., Wals, K., Antrobus, R., Göttgens, B., Dougan, G., Dawson, M.A., Lehner, P.J. (2015)
GENE SILENCING. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells.
Science 348(6242): 1481-1485
Sponsor- John Briggs, Structural Studies
David Owen is a Wellcome Trust Principal Research Fellow based at the Cambridge Institute for Medical Research. In joint efforts with a number of other laboratories, his group use an integrated structure/in vitro/in vivo approach to study membrane trafficking along the endocytic system of mammalian cells. This involves trying to understand the molecular recognition processes that occur within, and allow the formation of, the protein coats of tubular vesicular carriers, which move between the cell surface, endosomes and degradative endolysosomes.
In collaboration with John Briggs’ group, the structures of minimal AP2/clathrin and retromer coats have been determined by cryo electron tomography: both systems are now being expanded to include more coat components. In collaboration with David Neuhaus’ NMR group, the regulation of both processes is being investigated using a combination of NMR, X-ray crystallography and high-resolution live cell imaging.
- Wrobel, A.G., Kadlecova, Z., Kamenicky, J., Yang, J.C., Herrmann, T., Kelly, B.T., McCoy, A.J., Evans, P.R., Martin, S., Müller, S., Salomon, S., Sroubek, F., Neuhaus, D., Höning, S., Owen, D.J. (2019)
Temporal Ordering in Endocytic Clathrin-Coated Vesicle Formation via AP2 Phosphorylation.
Dev Cell 50(4): 494-508.e11
- Kovtun, O., Leneva, N., Bykov, Y.S., Ariotti, N., Teasdale, R.D., Schaffer, M., Engel, B.D., Owen, D.J., Briggs, J.A.G., Collins, B.M. (2018)
Structure of the membrane-assembled retromer coat determined by cryo-electron tomography.
Nature 561(7724): 561-564
Sponsor:- Greg Jefferis, Neurobiology
Gerald Rubin is a Senior Group Leader at the Howard Hughes Medical Institute’s Janelia Research Campus. His research focuses on developing an experimental approach to neurobiology based on the comprehensive identification and manipulation of individual cell types and circuit components. His laboratory uses the tools and methods they develop to study the neuronal circuits in Drosophila underlying learning and memory, sleep regulation, visual perception, sensory integration, and aggression. With Greg Jefferis’ group they are working, as part of a large international collaboration, to determine the complete wiring diagram – or connectome – of the adult Drosophila nervous system and to use that wiring diagram to gain insights into how the brain controls behavior.
Schretter, C.E., Aso, Y., Dreher, M., Robie, A.A., Dolan, M.-J., Chen, N., Ito, M., Yang, T., Parekh, R., Rubin, G.M. (2020)
Neuronal circuitry underlying female aggression in Drosophila
- Wu, M., Nern, A., Williamson, W.R., Morimoto, M.M., Reiser, M.B., Card, G.M., Rubin, G.M. (2016)
Visual projection neurons in the lobula link feature detection to distinct behavioral programs.
- Aso, Y., Rubin, G.M. (2016)
Dopaminergic neurons write and update memories with cell-type-specific rules.
Sponsor- Jan Löwe, Structural Studies
Kim Nasmyth currently holds the Whitley Chair at the Department of Biochemistry, University of Oxford and is a fellow of Trinity college. He was a PhD student in Mitchison’s lab in Edinburgh (1974-77), a post doc in Seattle Washington (1978-1980), a Robertson research fellow at Cold Spring Harbor (1980-81), and a member of staff at the MRC laboratory for molecular biology in Cambridge (1982-87) before moving to the Research Institute of Molecular Pathology (I.M.P) in Vienna, where he was a senior scientist from 1988 to 1997 and director from 1997 to 2006. His lab identified the cohesin complex that regulates the topology of eukaryotic chromosomes during interphase and holds sister chromatids together following their genesis during S phase. They also elucidated the mechanism by which cohesion is destroyed at the metaphase to anaphase transition, namely cleavage of cohesin’s kleisin subunit by separase, a thiol protease activated through ubiquitinylation of its inhibitory chaperone securin by the Anaphase-promoting complex or cyclosome. Kim’s lab has collaborated closely with that of Jan Löwe for nearly twenty years. Their analyses of cohesin’s structure have led to the notion that it holds sister DNAs together by entrapping them inside a tripartite ring formed by pairwise interactions between its Smc1, Smc3, and kleisin subunits. Their most recent work together has revealed aspects of the complex that enable it to compact DNAs through loop extrusion, in particular the ATP-dependent clamping of DNAs onto top of the Smc1/3 ATPase domains by a regulatory subunit called Scc2 (Nipbl). Kim’s work has been recognized by several awards, including the Gairdner foundation prize and the Breakthrough prize. He is a fellow of the Royal Society, a member of the Austrian Academy of Sciences, and a foreign honorary member of the American Academy of Arts and Sciences.
- Collier, J.E., Lee, B.G., Roig, M.B., Yatskevich, S., Petela, N.J., Metson, J., Voulgaris, M., Gonzalez Llamazares, A., Löwe, J., Nasmyth, K.A. (2020)
Transport of DNA within cohesin involves clamping on top of engaged heads by Scc2 and entrapment within the ring by Scc3.
- Srinivasan, M., Fumasoni, M., Petela, N.J., Murray, A., Nasmyth, K.A. (2020)
Cohesion is established during DNA replication utilising chromosome associated cohesin rings as well as those loaded de novo onto nascent DNAs.
- Petela, N.J., Gligoris, T.G., Metson, J., Lee, B.G., Voulgaris, M., Hu, B., Kikuchi, S., Chapard, C., Chen, W., Rajendra, E., Srinivisan, M., Yu, H., Löwe, J., Nasmyth, K.A. (2018)
Scc2 Is a Potent Activator of Cohesin's ATPase that Promotes Loading by Binding Scc1 without Pds5.
Mol Cell 70(6): 1134-1148.e7
Sponsor:- Jason Chin, PNAC
Tom Ellis is Professor of Synthetic Genome Engineering in the Bioengineering Department of Imperial College London and an Associate Faculty member of the Wellcome Trust Sanger Institute. Tom obtained his PhD in Cambridge studying the molecular sequence recognition at promoter regions. He then established a career in synthetic biology, leading a group since 2010 that develops tools and technologies for designing and assembling diverse genetic programs into microbial cells including yeasts. Since 2013, he has been part of the Synthetic Yeast Genome (Sc2.0) Project, an international collaboration rewriting the S. cerevisiae genome from computationally-designed synthetic DNA fragments. In collaboration with the Chin and Sale labs in PNAC, Prof Ellis is now developing the methods to achieve genome assembly from synthetic DNA in more complex cells, with a particular focus on chromosome synthesis in human cell lines.
- Ostrov, N., Beal, J., Ellis, T., Gordon, D.B., Karas, B.J., Lee, H.H., Lenaghan, S.C., Schloss, J.A., Stracquadanio, G., Trefzer, A., Bader, J.S., Church, G.M., Coelho, C.M., Efcavitch, J.W., Güell, M., Mitchell, L.A., Nielsen, A.A.K., Peck, B., Smith, A.C., Stewart, C.N., Tekotte, H. (2019)
Technological challenges and milestones for writing genomes.
Science 366(6463): 310-312
- Shaw, W.M., Yamauchi, H., Mead, J., Gowers, G.F., Bell, D.J., Öling, D., Larsson, N., Wigglesworth, M., Ladds, G., Ellis, T. (2019)
Engineering a Model Cell for Rational Tuning of GPCR Signaling.
Cell 177(3): 782-796.e27
- Blount, B.A., Gowers, G.F., Ho, J.C.H., Ledesma-Amaro, R., Jovicevic, D., McKiernan, R.M., Xie, Z.X., Li, B.Z., Yuan, Y.J., Ellis, T. (2018)
Rapid host strain improvement by in vivo rearrangement of a synthetic yeast chromosome.
Nat Commun 9(1): 1932