The Wellcome/ Cancer Research UK Gurdon Institute Prospectus 2020/2021 25 YEARS

The Wellcome/ Cancer Research UK Gurdon Institute

Studying Prospectus 2020/2021

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N D E R E R understand disease C HA R T The Gurdon Institute 3 Contents Welcome

Welcome to our new Prospectus, where we highlight our Watermark, the first such award in the University. Special activities for - unusually - two years: 2019 and 2020. The thanks for this achievement go to Hélène Doerflinger, COVID-19 pandemic has made it an extraordinary time Phil Zegerman and Emma Rawlins. Director’s welcome 3 Emma Rawlins 38 for everyone. I want to express my pride and gratitude for the exceptional efforts of Institute members, After incubating Steve Jackson's company Adrestia in About the Institute 4 Daniel St Johnston 40 who have kept our building safe and our research the Institute for two years, we wished them well as they progressing; this applies especially to our core team, moved to the Babraham Research Campus. We also sent COVID stories 6 Ben Simons 42 whose dedication has been key to our best wishes to Meri Huch and our continued progress. As you will Rick Livesey and their labs, as they Highlights in 2019/2020 8 Azim Surani 44 see, there is much to be excited embarked on their new positions in about in our research and activities. Dresden and London, respectively. Focus on research Iva Tchasovnikarova 46 It was terrific to see Gurdon I'm delighted that Emma Rawlins Group leaders Fengzhu Xiong 48 members receive recognition for was promoted to Senior Group their achievements. Steve Jackson Leader and that two new Group Julie Ahringer 20 Philip Zegerman 50 received the Leopold Griffuel Leaders joined us in Autumn Award in Translational and Clinical 2020. Iva Tchasovnikarova studies Andrea Brand 22 Associate group leaders Research, and the Royal Society epigenetic pathway mechanisms Mullard Award. Hansong Ma was and how they are disrupted in David Fernandez-Antoran 24 Martin Howard 52 awarded a Philip Leverhulme disease, while David Fernandez- Jenny Gallop 26 John Perry 54 Prize and selected as an EMBO Antoran's research is focused on Young Investigator, I received the cell competition and the impact of John Gurdon 28 Facilities 56 Genetics Society of America's ionising radiation on selection. George W. Beadle Award, and Office Manager Lynda Steve Jackson 30 Support staff 58 Lockey was named the Unsung Heroine of Professional Finally, I'm pleased to welcome two new Associate Group Services. We are also excited that a major component of Leaders. John Perry (MRC Epidemiology Unit) uses Tony Kouzarides 32 Seminars, events and the Wellcome-funded Human Developmental Biology human genetics to understand disease mechanisms, and publications in 2019/2020 60 Initiative is based in the Institute, led by Emma Rawlins, Martin Howard (John Innes Centre) builds mathematical Hansong Ma 34 Ben Simons and Azim Surani. models of biological processes. We look forward to Acknowledgements 77 exciting and productive interactions with them. Eric Miska 36 I'm especially proud that our exceptional Public Engagement was recognised by a Silver Engage

Director February 2021 4 About the Institute About the Institute

The Wellcome/ Cancer Research UK Gurdon Institute is a world-leading centre for research at the interface between developmental biology and cancer biology.

Our research is focussed in four overlapping areas:

our focus

Cell division, Function and regulation Mechanisms of cell Cell biological proliferation and of the genome and fate determination, processes underlying genome maintenance epigenome multipotency and organ development plasticity and function and interactions across Cambridge’s • A wealth of stimulating Join us vibrant research environment, seminars and masterclasses, We have a thriving community of including through department an annual Institute retreat, graduate students and postdocs affiliations and teaching. and Institute postdoc and PhD who contribute to and benefit from student groups (pp. 62–65) our exciting research environment. We investigate these areas in both findings have been successfully sources including national and We benefit from: • Award-winning public We welcome enquiries from those normal development and cancer translated to drug discovery international governmental and • Core facilities with state-of- engagement between our interested in joining us, which can using multiple model systems, from through spinout companies. charitable grants. Scientific progress the-art equipment and support scientists and the wider public be done by writing to the relevant yeast to human organoids (pp. and future plans are assessed at including super-resolution (pp. 16–17). group leader. 20–50). The Gurdon Institute’s principal regular intervals by our International microscopy, next-generation • An on-site canteen, social sponsors are Wellcome and Cancer Scientific Advisory Board (p. 77) . sequencing and bioinformatics events and sports groups, which Find out about the latest Since our formation in 1991, our Research UK, who support our (pp. 56–57) enhance our welcoming and opportunities on our website. research has led to major insights excellent infrastructure through core The Institute is embedded within • Central services providing inclusive environment. into the molecular and cellular grants, and our research through the University of Cambridge, administration, computing and • An Athena SWAN Bronze Award defects that give rise to cancer direct grants to group leaders. Our providing unparalleled IT, stores, media preparation for promoting equality and and other diseases of ageing, and research is also funded by other opportunities for collaborations and glass-washing. diversity across our workforce. 6 COVID stories The Gurdon Institute 7

quickly increased, with home tests “Then, of course, there was the arriving from all over the country, wider shortage across the country, we were pushed to the limit and at so Charles and I looked at what we COVID stories one point caused a bottleneck of could do.” the whole pipeline. The solidarity Once our building opened again and sense of responsibility of on 15th June under University everyone in the team meant that we What did we do during the coronavirus pandemic in 2020? guidance, the two set up a no-touch would ensure all the samples were log-in log-out system allowing the processed each day, and Along with institutions and Some of our scientists paediatrician at Addenbrooke’s The roles taken by Weronika Fic, we know Institute to track numbers of people businesses across England, the re-focussed their research Hospital from March to September. Dmitry Nashchekin, Helen Zenner we played an important part in on site in real time, ensuring we Institute shut its doors at 5pm on Omer Ziv with Miska lab colleagues It was actually quite nice to have and Mihoko Tame (St Johnston lab) helping contain the first COVID-19 stuck to the strict rules on numbers .” 20th March for Lockdown 1.0. Only and collaborators at Justus Liebig something to do during that first and Paolo Amaral (Kouzarides lab) wave in different lab spaces. minimal maintenance and technical University worked to produce a lockdown, although being coughed were in sample preparation, RT-PCR staff remained, regularly checking map and database of the short on by feverish children all day wasn’t tests and data analysis, the full team the building and the fly stocks, and long-range interactions of ideal!” eventually processing over 8000 while researchers could no longer the SARS-CoV-2 RNA genome nasopharyngeal swab samples daily. access their benches and had to (details in ‘Research highlights call a sudden halt to hundreds of 2020’). Ben Simons was involved in experiments. Administrative staff epidemiological modelling. took computers and files home.

And that’s how it remained until 15th June when we re-opened at one quarter occupancy, slowly moving up to 50% occupancy by September. Many different staff, and especially researchers, were delighted to return once more to the building. Lockdown 2.0 in Core staff made Personal November sent some more staff Protective Equipment: Alex back home again. Sossick and Charles Bradshaw of the Imaging and Bioinformatics Family members sewed face The core staff have done an teams each took home a 3D printer. coverings: The mother of a staff incredible job to keep as much of The machines were set up to run member sent about 600 of her the Institute open and functioning 24-hours a day, making in total hand-sewn, eco-friendly and as possible (and legal) at all times, Five researchers worked shifts 500 visor headbands, which were washable face coverings all the way in terms of maintenance and safety distributed locally to key workers from her village in Italy, enough for in the building, supplying media, as volunteers at the Cambridge that ran seven days in GP surgeries, hospitals and care everyone to have two each. and enabling computing services for Others intermitted from research Testing Centre Ben a week from 6am to midnight to homes. “The Institute had given a remote working. Meanwhile, other and returned to the clinic: Paolo recalls: “Volunteering at the Fisher (Miska lab) says “I returned support the national effort to boost lot of our own PPE, especially visors, Institute members have contributed centre felt like a call of duty. As the to full-time clinical work as a COVID-19 testing capacity. to Addenbrookes,” says Alex. directly to fighting the pandemic: number of samples to be processed 8 About the Institute The Gurdon Institute 9

Highlights in 2019/2020 10 Awards The Gurdon Institute 11 Awards

Feb '19: Steve Jackson receives Three of the Institute’s labs are November and Steve Jackson is cancer research prize among more than a dozen across among them, awarded funding the UK working together to for a project on the DNA damage The 47th ARC Foundation generate data, develop new tools response in collaboration with Léopold Griffuel Award in and build a ‘family tree’ of cell partners in Switzerland and Austria. Translational and Clinical Research was presented to Steve Jackson at a divisions during development, This was the first of the new ceremony in Paris on 10th April. The starting at fertilisation. Azim Surani is Horizon 2020 grants to come to award was given "for his work on a co-lead for ‘cell lineage in human Cambridge. DNA damage repair and his role in epiblast specification and early the development of medicines such differentiation’; Emma Rawlins is a Dec '19: Song for the Unsung as PARP1 and 2 inhibitors used [for] co-lead for ‘human lineage analysis Heroine cancer treatment." in a 3D spatial context: cardio- The Institute's Office Manager, pulmonary system development’; Lynda Lockey, won the Unsung and Ben Simons is a lead for one May '19: Pisa Honorary Doctorate Heroine Award in the University of three cross-cutting technology for John Gurdon of Cambridge Professional platforms – computational biology . John Gurdon received a Doctorate Services Recognition Scheme and data analysis. Institute Director Julie Ahringer said Honoris Causa in Translational "Lynda is a very deserving recipient Medicine from the Scuola Superiore Sant’Anna of Pisa. He gave a lecture Sep '19: Meri Huch wins BINDER of the award...Her dedicated and there and at Bologna University. Innovation Prize understated work makes things run by the Leverhulme The awardees join a four-year While in Bologna he was interviewed The 2019 BINDER Innovation smoothly, and positively impacts Aug ‘20: Award for research Prize 2020 Trust. The prizes of £100,000 programme that provides financial by national newspaper 'Il Resto del Prize was awarded to Group everyone". contributing to national prosperity "recognise the achievement of support, training and networking Carlino'. Leader Meri Huch for her research The Royal Society Mullard Award outstanding researchers whose work opportunities. on liver organoids for the study Jan ‘20: Ahringer honoured by 2020 was awarded to Steve Jackson of liver biology and disease. The has already attracted international Jul '19: Gurdon researchers in Genetics Society of America for his research that led to the award is given for "outstanding cell recognition and whose future career Dec ’20: Aztekin wins ELISIR Wellcome’s new £10M project on Julie Ahringer was honoured with discovery of the drug olaparib, biological research with a focus on is exceptionally promising". scholarship at EPFL human development the Genetics Society of America's which has reached blockbuster cell culture," and awarded by the status for the treatment of ovarian PhD student in the Gurdon lab, The George W. Beadle Award Human Developmental German Society for Cell Biology. and breast cancers. Dec ‘20: Ma selected as EMBO Can Aztekin, moves directly to an aims to provide "for outstanding contributions Biology Initiative Young Investigator independent principal researcher insights into how humans develop – to the community of genetics Hansong Ma was selected as one of position at the Swiss Federal Institute from one cell to billions of different Nov '19: Steve Jackson awarded researchers...beyond an exemplary Oct ‘20: Philip Leverhulme Prize 30 new , of Technology in Lausanne (EPFL), as cells that make up our tissues and ERC Synergy Grant research career". for Ma EMBO Young Investigators judged to be "among the next an organs. Recipients of the ERC Synergy Hansong Ma was awarded a EPFL Life Sciences Independent generation of leading life scientists". Grants were announced in prestigious Philip Leverhulme Research (ELISIR) scholar. 12 Research highlights The Gurdon Institute 13

liver diseases where regeneration is an 'epitranscriptomic' pathway with nucleocytoplasmic transport, impaired. effects on lung cancer cell behaviour uncovering new links between Research in 2019 Aloia L et al. (2019) Nature Cell in vitro. They developed a different forms of dementia. Biology 21: 1321–1333. technique to precisely locate which Paonessa F et al. (2019) Cell Reports guanosine on a micro RNA called 26: P582–593.E5. let-7 was modified with a methyl does not depend on the protein generation DNA sequencing group, regulating its processing and downstream action to suppress cell H2AX. They show that MDC1, to over 4500 yeast strains in the Jelly secretion migration. RNA uptake to with RNA which was previously believed to Gene Knockout Collection. The the feeding glands Pandolfini L, Barbieri I et al. (2019) Jelly work only when interacting with resulting comprehensive resource with phosphorylated H2AX, in fact identifies new genes responsible Molecular Cell 74: P1278–1290.E9. RNA retains its capacity to recruit repair for maintaining the stability of DNA factors to the site of DNA damage in cells, and whose absence or even when H2AX is absent. This mutation leads to a variety of effects, Brain location determines stem may enable DNA repair in areas of from changes in short sequence cell activation speed the genome known to be depleted repeats to the loss of whole Otsuki and Brand revealed that of H2AX. chromosomes. These 'mutational stem cells activate rapidly or slowly Salguero I et al. (2019) Nature signatures' can now also be studied systemic depending on where they reside RNA spread Communications 10: 5191. in human cells. in the brain. G2 quiescent stem RNA ingestion Puddu F et al. (2019) Nature 573: Fly gene provides clue to New cell type in tail cells, which activate first and have 416–420. RNA uptake to the hemolymph reversing mitochondrial disease regeneration high regenerative potential, reside Don't get your DNA in twist primarily in fruit fly ventral brain The Ma lab have identified a Transmissible RNA pathway in Researchers in the Gurdon and regions. G0 quiescent stem cells are protein in fruit flies (Drosophila) The Zegerman lab’s new publication Simons labs working under honey bees shows that limiting the rate of DNA more numerous in the dorsal brain. that can be targeted to reverse Jerome Jullien identified a new The Miska lab's Eyal Maori along duplication - by limiting the number This is an important consideration in the effects of disease-causing cell type involved in regeneration with colleagues in UK, Israel and of DNA replication initiation events designing regenerative therapies. mutations in mitochondrial genes. of tadpole tails. They've named the USA have discovered a pathway - is important to prevent intertwining Otsuki L & Brand AH (2019) The discovery could provide clues the Regeneration-Organizing Cells by which honey bees share RNA between the newly replicated Developmental Cell 49: 1–8. about how to counteract human for their role in promoting and through secretion and ingestion of chromosomes. This work may be mitochondrial diseases, for which coordinating new tissue growth after worker and royal jellies, offering a relevant for the treatment of cancer there is currently no cure. How to boost adult liver amputation, and hope to find clues in promising route for administering cells, which are characterised by Nuclear membrane dysfunction Chiang A C-Y et al. (2019) Current regeneration these cells to inform new approaches bee 'vaccines'. In addition, the high rates of DNA duplication. underlying dementia Biology 29: 1–7. to regeneration in mammals. researchers identified a specific Morafraile EC et al. (2019) A paper from the Huch lab - with Genes & Aztekin C et al. (2019) Science 364: The Livesey and Jackson groups protein in royal jelly that binds and 33: 21–22. collaborators in the Gurdon Institute, Development 653–658. pooled expertise, studying patient- protects the RNA in granules while UK and Germany - describes the Alternative DNA repair pathway derived neurons in the lab to outside the body. molecular mechanism triggered by for MDC1 investigate how mutations in the Maori E et al. (2019) TET1 that allows damaged adult Molecular Cell New DNA stability genes tau gene cause frontotemporal 74: P598–608.E6. Salguero and colleagues in liver cells to regenerate. This paves RNA modification pathway uncovered in systematic study dementia (FTD). They found that, in the Jackson lab have found an the way for design of drugs to affects cancer cell migration of Yeast Knockout Collection FTD neurons, microtubules deform alternative pathway to elicit the boost regeneration in conditions Researchers in the Kouzarides lab the nuclear membrane and perturb DNA-damage response that The Jackson lab applied next- such as cirrhosis or other chronic and colleagues have characterised 14 Research highlights The Gurdon Institute 15

collaborative studies by the Simons lab have shown - at single-cell resolution - how stem cells react Research in 2020 to regenerate tissue and restore homeostasis. Stretching induces skin expansion by creating a transient bias in the renewal activity transcription factor Ascl1, which is and Simons labs. These organoids of epidermal stem cells, while a Long-range interactions in SARS- a determinant for nerve, resides grown in chemically defined culture second subpopulation of basal CoV-2 RNA progenitors remains committed to Sperm populations show on chromatin to direct gene medium provide an important Omer Ziv from the Miska lab, in differentiation. homogeneous epigenetic marks expression. While previous studies model for research into the healthy collaboration with Justus-Liebig Aragona M et al. (2020) 584: Gurdon lab and colleagues, led by suggest that residency times are and diseased pancreas, including Nature University colleagues, has revealed 268–273. Jerome Jullien, examined histones only seconds or minutes, this conditions such as cystic fibrosis, precise details of the base-pairing in sperm to uncover a conserved experiment showed a long-term pancreatitis, cancer and diabetes. patterns formed by the long RNA mechanism for transmission of association of hours or days, which Georgakopoulos N et al. (2020) genome of the SARS-CoV-2 virus, epigenetic information to the could explain the stability of cell BMC Developmental Biology 20: 4. responsible for the COVID-19 embryo. As sperm develop they fate commitment. pandemic. Ziv devised the method lose a large proportion of the Gurdon JB et al. (2020) Proc Natl that takes a snapshot of both short- histones found in somatic cells, Acad Sci 117 (26): 15075-15084. and long-range interactions in the Tailless/TLX directs cell fate but the remainder are retained RNA, which are essential for viral change in tumourigenesis in the same position across the function and therefore present sperm population, indicating the Hakes and Brand uncover the cell potential therapeutic targets. How inflammation affects potential to prime transcription for fate changes that occur during Ziv O et al. (2020) 80 regeneration embryonic development. Molecular Cell brain tumour initiation. They (6): 1067-1077.E5 Why can regeneration-incompetent show that high levels of Tailless/ Oikawa M et al. (2020) Nat Comms tadpoles not regenerate their TLX, known to be associated Cancer drug hope for genetic 11: 349. tails? The Gurdon lab show that with aggressive glioblastomas, disease immune cells behave differently revert intermediate progenitors to Berquez, Gadsby, Festa and Gallop Gene regulatory architectures in for regeneration-competent and neural stem cells as a first step to lab colleagues discovered that Embryo polarisation link to cell germline and somatic tissues -incompetent tadpoles. Successful tumourigenesis. Their findings also adjusting membrane composition cycle Jacques Serizay and Ahringer lab suppression of inflammation is support enforced differentiation as with the PI3K inhibitor alpelisib colleagues profiled and compared The Zegerman lab, with Gurdon required for the multiple cellular an effective treatment for Tailless/ rebalances actin cytoskeletal transcriptional and regulatory Institute colleagues, provided the mechanisms necessary for new tail TLX-induced brain tumours. organisation in cell culture and element activities across five tissues first direct molecular mechanism growth. Hakes AE & Brand AH. (2020) Elife alleviates absorption defects in of the adult nematode worm, C. through which polarisation of the Aztekin C et al. (2020) 9: e53377. an in vivo mouse model of Lowe elegans. The results demonstrate Development embryo is coordinated with DNA 147: dev.185496. syndrome/Dent disease. Their fundamental differences in Pancreas organoids to model replication initiation factors, linking findings provide proof-of-concept regulatory architectures of germline disease developmental cues with changes for the first disease-modifying and somatic tissue-specific genes, How does stretching skin make in the cell cycle, in the nematode C. Pancreas organoids can be treatment. and provide a tissue-specific Is TF residency time the key to it grow? elegans. successfully generated from single Berquez M et al. (2020) resource for future studies. cell fate commitment? Kidney Gaggioli V et al. (2020) cells, or fresh and frozen tissue, By tracing the dynamics of cells 98 (4): 883-896. PLoS Serizay J et al. (2020) International 16 (12): e1008948. Genome Res The Gurdon lab used a competition then expanded and maintained during stretch-mediated expansion Genetics 30: 1752–1765. assay to test how long the long-term in culture, say the Huch of the mouse skin epidermis, 16 Public engagement Public engagement

Mission: to make our fundamental classrooms with support for teachers biological research accessible and students to deepen their and responsive to the public for knowledge of fundamental biology the mutual benefits of inspiration, and current research. Teachers knowledge-exchange and trust. and our scientists co-created four innovative teaching 'toolkits', free to use in classrooms across the UK: The Cell Explorer (online temporary tattoos. Visitors to Institute provided accommodation, Sixth-form workshops interactive 3D cell model), festivals and events could choose travel expenses and food to all Our Sixth-form workshops aim to Explore Epigenetics a tattoo from our collection of participants. Students told us "It inspire A-level biology students. (an online designs and then have a chance gave me an experience hard to find State schools from across the game about to discuss the research with the elsewhere" and "I learned that I can country can bring groups of Year 12 epigenetics), scientist applying their tattoo. become a scientist." biology students to the Institute to Generate increased trust in fundamental a kit for Fruit research and ensure our research remains Afterwards, they could show off learn about our research. The visit Fly Larvae relevant to society their new tattoo to friends and Stitching Science includes a tour of our facilities, a Empower Dissection share their new science knowledge. The Public Engagement Seed seminar about the history of science and inspire (teaching Public Thank you to the Wellcome Centre Fund Project for 2019 was devised and the future of cancer research, a Public the next about the engagement generation for Cell Biology in Edinburgh for and led by Stephanie Norwood, hands-on workshop where students Engagement size and strategy sharing their idea! a former PhD student. The can test their skills at identifying strategy scale of project aims to create an informal cancerous tissue with microscopes, cells, tissues Aspiring Scientists Training environment for scientists to and a Q&A with our PhD students. and organs) Programme interact with local communities and Unlocking Providing an inspiring, immersive and learn a new craft, disseminate Embed public Genetic Editing (a experience to encourage groups information about research engagement in hands-on problem- research culture that are underrepresented in projects, and increase public trust Silver Engage solving game). The science, we welcomed 11 Sixth- in fundamental research. The Watermark project was funded by form students for a week at the project engaged crafters through a The Gurdon Institute Wellcome and evaluated by the Institute. Students attended series of knitting workshops, craft was awarded a Silver Our projects in 2019 to support University of Cambridge Faculty of morning workshops about scientific fairs and other events. Participants Engage Watermark in the public engagement strategy Education. SCoPE website: topics or presentation skills. Then create a detailed crochet cell December 2020, the first such award included: https://scopegurdoninstitute.co.uk they spent the rest of the day in a containing various organelles at the University of Cambridge. The lab to talk with lab members about (mitochondria, cytoplasm and Silver Engage Watermark, awarded Scientists' Collaborative Project Tattoo My Science their research and science careers. membrane) and discuss the by the National Co-ordinating Centre with Educators (SCoPE) Our scientists created designs The project was funded by the different parts of the cell with for Public Engagement, recognises We aim to bring contemporary based on their biology research, University of Cambridge Widening scientists as they knit. Website: the Institute's “robust and committed research into GCSE and A-level and we turned these into fun, Participation Project. The Gurdon https://bitly.com/StitchingSci approach to public engagement”. 18 Activities and impacts in 2019 The Gurdon Institute 19

Focus on research 20 Group leaders The Gurdon Institute 21

JULIE AHRINGER Developmental regulation of chromatin structure and function H3K9me2 2-cell 6-cell 32-cell 200-cell How is chromatin regulated to direct correct gene expression programmes? Animal development is a remarkable process during which a single-celled totipotent zygote produces a myriad of different cell types. A driving force is the differential control of chromatin activity, which establishes gene expression programmes that drive cellular identity. Deciphering this control is necessary for understanding how the genome directs development and the diseases that result from chromatin dysregulation.

We study how cell-type specific gene expression and chromatin organisation are achieved using the simple C. elegans model, focusing on controls and interactions at regulatory elements, the formation and function of euchromatin and heterochromatin, and the regulation of 3D nuclear organization. Taking advantage of the experimental amenability and defined lineage of C. elegans, we apply high-throughput genomics, DAPI super-resolution microscopy, single-cell analyses, and computational approaches to understand core mechanisms of gene expression regulation in development.

Selected publications: Heterochromatin in early Serizay J et al. (2020) Tissue-specific profiling reveals distinctive regulatory development in C. elegans architectures at ubiquitious, germline and somatic genes. BioRxiv DOI: Embryonic nuclei imaged 10.1101/2020.02.20.958579v1. using STED super-resolution Janes J et al. (2018) Chromatin accessibility dynamics across C. elegans microscopy reveals that development and ageing. Elife 7:e37344. H3K9me2 is found in McMurchy AN et al. (2017) A team of heterochromatin factors collaborates distinct foci. Co-workers: Alex Appert, Francesco with small RNA pathways to combat repetitive elements and germline Carelli, Marie de la Burgade, Yan stress. Elife 6:e21666. Dong, Martin Fabry, Andrea Frapporti, Rhys McDonough, Arianna Pezzuolo, Evans KJ et al. (2016) Stable C. elegans chromatin domains separate Roopali Pradhan, Anna Townley, broadly expressed and developmentally regulated genes. Proc Natl Acad Ser van der Burght, Connie Xiao Sci USA 113(45): E7020–7029. 22 Group leaders The Gurdon Institute 23

ANDREA BRAND Time to wake up: regulation of stem cell quiescence and proliferation

Stem cell populations in tissues as varied as blood, gut and brain spend much of their time in a mitotically dormant, quiescent, state. A key point of regulation is the decision between quiescence and proliferation. The ability to reactivate neural stem cells in situ raises the prospect of potential future therapies for brain repair after damage or neurodegenerative disease. Understanding the molecular basis for stem cell reactivation is an essential first step in this quest.

In Drosophila, quiescent neural stem cells are easily identifiable and amenable to genetic manipulation, making them a powerful model with which to study the transition between quiescence and proliferation. These stem cells exit quiescence in response to a nutrition-dependent signal from the fat body, a tissue that plays a key role in the regulation of metabolism and growth. My lab combines cutting-edge genetic and molecular approaches with advanced imaging techniques to study the reactivation of Drosophila neural stem cells in vivo. This enables us to deduce the sequence of events from the level of the organism, to the tissue, the cell, and finally the genome.

Selected publications: Hakes AE & Brand AH (2020) Tailless/TLX reverts intermediate neural progenitors to stem cells driving tumourigenesis via repression of asense/ ASCL1. Elife 9:e53377. Otsuki L& Brand AH (2019) Dorsal-ventral differences in neural stem cell quiescence are induced by p57KIP2/Dacapo. Dev Cell 49(2): 293-300.e3. Otsuki L & Brand AH (2018) Cell cycle heterogeneity directs the timing of Co-workers: Neha Agrawal, Diana Arman, neural stem cell activation from quiescence. Science 360: 99–102. Maire Brace, Catherine Davidson, Bernardo Delarue Bizzini, Alex Donovan, Amy Cheetham SW & Brand AH (2018) RNA-DamID reveals cell-type-specific Foreman, Thomas Genais, Leia Judge, Oriol binding of roX RNAs at chromatin-entry sites. Nat Struct Mol Biol 25:109–114. Llorà Batlle, Anna Malkowska, Tara Srinivas, The developing visual system Jocelyn Tang, Christine Turner, Marloes van Wezel, Rebecca Yakob, Nemira Zilinskaite The Drosophila central brain (red and blue) and eye imaginal disc (green and red) with dividing cells labelled in white (van den Ameele and Brand). 24 Group leaders The Gurdon Institute 25

DAVID FERNANDEZ-ANTORAN Radiation biology and cell competition

How does ionising radiation affect tissue homeostasis? Healthy adult epithelial tissues progressively accumulate clones of cells carrying mutations implicated in cancer. Expansion of the clones follows Darwinian evolution rules, where some mutations can increase cell fitness and promote the growth of clones at the expense of the non- mutated normal adjacent cells, in a process of clonal competition.

Ionising radiation has long been studied as one of the most common environmental mutagenic agents that promotes tumour formation by damaging DNA and creating new oncogenic mutations. However, little is known about its effects on clonal evolution and tissue dynamics. We have recently shown that radiation can act as an environmental selective pressure, affecting cell competition mechanisms and promoting expansion of pre-existing oncogenic mutations, which might increase the risk of cancer development.

We use long-term human and mouse 3D primary epithelial cultures, in vivo cell lineage tracing, mathematical modelling, next generation sequencing methods and state-of-the-art confocal microscopy techniques to unravel the molecular responses and the cellular interactions that control normal and mutant cell behaviours after exposure to ionising radiation.

Our final aim is to set the basis for designing external interventions that can modulate cell competition outcomes during radiation exposure, eliminate oncogenic mutations and reduce the risk of cancer initiation and progression.

Co-workers: Inês Ferreira, Jose Selected publications: Antonio Valverde-Lopez Fowler JC et al. (2020) Selection of oncogenic mutant clones in normal human skin varies with body site. Cancer Discov DOI: 10.1158/2159-8290.CD-20-1092. Piedrafita G et al. (2020) A single-progenitor model as the unifying paradigm of The fight for space during ionising radiation exposure epidermal and esophageal epithelial maintenance in mice. Nat Comms 11: 1429. This rendered image shows an irradiated mouse oesophageal epithelium populated by fitter oncogenic Fernandez-Antoran D et al. (2019) Outcompeting p53-mutant cells in the mutant clones (green) that are expanding at the expense of non-mutated normal adjacent cells. Proliferation normal esophagus by redox manipulation. Cell Stem Cell, 25: 329–341.e6. markers are shown in white and red; cell nuclei in blue. 26 Group leaders

JENNY GALLOP Signalling to the actin cytoskeleton

How do cells control their movement? Cells move during embryonic development and throughout the life of an organism. When they move, cells reorganise a system of filaments - the actin cytoskeleton - that gives them their shape and exerts force on the surrounding tissues. When regulation of the actin cytoskeleton is disrupted it can lead to cancer metastasis, intellectual disability, kidney dysfunction and other problems.

We study how the actin cytoskeleton is assembled in different ways. The cell membrane is an important site of control of actin rearrangements because it is the boundary between the outside and inside of the cell and is responsible for initiating communication between and within cells, which is called signalling.

We have developed cell-free systems using phospholipid bilayers and frog egg extracts that allow us to find out how signalling lipids in the cell membrane precisely control the molecular events of actin assembly. We use combine these cell-free systems with the use of fruit flies, frog embryos and cultured human cells to test and generate hypotheses about the molecular events underlying actin regulation during development and disease.

Selected publications: Berquez M et al. (2020) The phosphoinositide 3-kinase inhibitor alpelisib restores actin organization and improves proximal tubule dysfunction in vitro and in a mouse model of Lowe syndrome and Dent disease. Kidney Int. 98: 883–896. Watching filopodia grow Jarsch IK et al. (2020) A role for SNX9 in the biogenesis of filopodia. Co-workers: Thomas Blake, Jonathan J Cell Three-dimensional reconstruction of filopodia-like structures growing from a supported lipid bilayer. The Gadsby, Pantelis Savvas Ioannou, Biol 219(4): e201909178. structures were segmented based on fluorescent actin intensity in a stack of microscopy images of size 76.13 x Julia Mason, Kathy Oswald, Kazimir Richier B et al. (2018) Integrin signaling downregulates filopodia during 76.13 x 30 microns. Uzwyshyn-Jones, Pankti Vaishnav muscle-tendon attachment. J Cell Sci 131: jcs21733. Colours were randomly assigned as a guide for the eye. The segmentation was performed using a custom Daste F et al. (2017) Control of actin polymerization via the coincidence of image-analysis pipeline. phosphoinositides and high membrane curvature. J Cell Biol 216: 3745–3765. 28 Group leaders The Gurdon Institute 29

JOHN GURDON Somatic cell nuclear transfer in Amphibia Nuclear reprogramming by oocytes and eggs Nucleus of differentiated cell Transplanted nucleus 1 year 2 days and egg cytoplasm Can we make cell reprogramming more efficient? Our group focuses generate wide range of on somatic cell nuclear transfer to amphibian eggs and oocytes from different cell types two complementary points of view. One aims to identify the molecules unfertilised and tadpole frog and mechanisms by which the cytoplasm of an egg or oocyte can enucleated egg reprogramme the nucleus of a differentiating somatic cell to behave like that of an embryo. From this state, many different kinds of cells for replacement can be generated. Nuclei of differentiated cells

The other aim is to identify the molecules and mechanisms that stabilise Transplanted nuclei have the differentiated state of somatic cells, as a result of which they resist 1 day 1 day changed donor gene reprogramming procedures. For these purposes we use single nuclear expression transfer to unfertilised eggs or multiple nuclear transfer to ovarian oocytes. oocyte and its injected nuclei nucleus enlarge We make use of the special properties of an amphibian oocyte to inject messenger RNA that codes for a transcription factor protein. When this Design of competition experiments to analyse transcription factor action using Xenopus oocytes has been synthesised, it concentrates in the oocyte nucleus. The next day we inject plasmid DNA directly into the oocyte nucleus, where the factor causes transcription, and later expression, of a reporter gene in the plasmid. 24 hrs 24 hrs 1-24 hrs Freeze and assay for reporter expression Selected publications: Gurdon JB et al. (2020) Long-term association of a transcription factor mRNA Plasmid DNA with Plasmid DNA as compe- with its chromatin binding site can stabilize gene expression and cell fate for Ascl1 an Ascl binding site titor with an Ascl binding commitment. Proc Natl Acad Sci USA 117: 15075–15084. and a Firefly site and a Renilla reporter reporter Aztekin C et al. (2019) Identification of a regeneration-organizing cell in the Xenopus tail. Science 364: 653–658. Co-workers: Hector Barbosa Triana, Dilly Bradford, Frances Connor, Nigel Hörmanseder E et al. (2017) H3K4 methylation-dependent memory of Garrett, Khayam Javed, Toshiaki somatic cell identify inhibits reprogramming and development of nuclear Molecules and mechanisms Shigeoka, Ming-Hsuan Wen transfer embryos. Cell Stem Cell 21: 135–143.e6. Top: Two types of nuclear transfer experiments, with eggs or oocytes. Bottom: The Xenopus oocyte can be used to provide a functional test for the binding of a cell-fate- determining transcription factor, such as Ascl1 for nerve. Once expression of the first plasmid DNA is established, a second plasmid is not able to compete because of the stable binding of the factor. 30 Group leaders The Gurdon Institute 31

STEVE JACKSON Maintenance of genome stability MDC1 has H2AX-independent roles in the DNA damage response

100 MDC1 DNA is constantly damaged by environmental and endogenously recruitment of arising agents. Cell survival and genome integrity are promoted repair factors 10 by the DNA-damage response (DDR), which detects, signals the H2AX presence of and repairs DNA damage. DDR defects are associated ATM 1 WT with developmental disorders, immunodeficiencies, infertility, P H2AX KO premature ageing and cancer. Our research aims to characterise the cell IR MDC1 KO Cell survival (%) H2AX/MDC1 KO biology and mechanisms of established and new DDR pathways and 0.1 components, and to apply this knowledge to better understand and 0 1 2 3 4 5 treat human diseases. H2AX IR dose (Gy)

We have taken the global approach of cataloguing the >4,500 knockout After DNA damage, phosphorylated histone H2AX recruits MDC1, Unexpectedly, eliminating MDC1 genes of the diploid yeast knockout collection, using next-generation allowing the accumulation of additional repair factors results in more DNA damage sequencing to identify those genes that have an impact on genome sensitivity than eliminating H2AX stability. Analysing this dataset revealed genes affecting repetitive element maintenance, and nuclear and mitochondrial genome stability, Repair factors, like 53BP1, accumulate at DNA damage sites even in the absence of H2AX, but this and showed how strains adapt to loss of non-essential genes. At the requires the PTS-repeat region of MDC1 other end of the scale spectrum, we determined what structural features of the DDR factors PALB2 and MDC1 associate with chromatin in ways MDC1 − wt MDC1 − ∆PST that are crucial for effective DDR in the absence of BRCA1 and H2AX, H2AX-free genomic regions respectively. ATM H2AX+/+ Selected publications: Belotserkovskaya R et al. (2020) PALB2 chromatin recruitment restores Co-workers: Samah Awad Diab, Rimma Belotserkovskaya, Ramsay Bowden, homologous recombination in BRCA1-deficient cells depleted of 53BP1. Chris Carnie, Julia Coates, Sabrina Nat Commun 11: 819. PST recruitment of Collier, Giuseppina D'Alessandro, Salguero I et al. (2019) MDC1 PST-repeat region promotes histone H2AX- -/- repair factors Muku Demir, Kate Dry, Yaron Galanty, independent chromatin association and DNA damage tolerance. H2AX Maryam Ghaderi Najafabadi, Nadia Nat 10: 5191. P Gueorguieva, Vipul Gupta, Soren Commun MDC1 Hough, Rebecca Lloyd, Donna Lowe, Puddu F et al., (2019) Genome architecture and stability in the 53BP1 David Morales, Francisco Muñoz Saccharomyces cerevisiae knockout collection Nature 537:416-420. Martinez, Domenic Pilger, Fabio Puddu, Helen Reed, Matylda Sczaniecka-Clift, Almudena Serrano Benitez, George Spooner, John Thomas, Andrea Voigt, Mike Woods, Guido Zagnoli-Vieira 32 Group leaders The Gurdon Institute 33

TONY KOUZARIDES

Epigenetic modifications and cancer Epigenetic targets for cancer therapy

Do enzymes that modify chromatin and RNA offer therapeutic targets? DNA exists in the cell nucleus wrapped around histone proteins to form chromatin. The DNA and histones are decorated with many types of covalent chemical modifications, which can affect RNA transcription and other cellular processes. In addition, non-coding RNAs that regulate chromatin function can be similarly chemically modified. histone-modifying RNA-modifying Our lab is involved in characterising the pathways that mediate and enzyme enzyme control DNA, RNA and histone modifications. We try to understand the cellular processes they regulate, their mechanism of action and their involvement in cancer.

Our focus at the moment is modifications of messenger RNA (mRNA) Post-transcriptional and non-coding RNA. There are very few modifications identified on control these low-abundance RNAs, unlike on transfer RNA and ribosomal RNA, where there are many. We have been developing sensitive technologies Transcriptional to detect modifications, such as specific antibodies, chemical reactivity control assays and mass spectrometry. Using these, we have been able to detect a number of novel modifications on mRNA and microRNA (short-length non-coding RNAs) and have shown that these function to regulate DNA mRNA translation and microRNA processing. Furthermore, we have shown that the enzymes that mediate these modifications are implicated modification in cancer. We are developing small-molecule inhibitors against some of these enzymes in collaboration with STORM Therapeutics. Co-transcriptional Selected publications: control Barbieri I & Kouzarides T (2020) Role of RNA modifications in cancer.Nat Co-workers: Minaam Abbas, Andrej Rev Cancer 20, 303–322. Alendar, Andrew Bannister, Francisco Pandofini L et al. (2019) METTL1 Promotes let-7 MicroRNA Processing via José Campos Laborie, Alistair Cook, m7G Methylation. 74(6): 1278-1290. The crucial role of modifications Elena Everatt, Marie Klimontova, Sri Mol Cell Bio Lestari, Nikki Mann, Carlos Melo, Barbieri I et al. (2017) Promoter-bound METTL3 maintains myeloid Gene expression can be regulated by chemical modifications before and during transcription, including of Helena Santos Rosa, Konstantinos leukaemia by m6A-dependent translation control. Nature 552: 126–131. non-coding RNA. Tzelepis, Daniel Wing 34 Group leaders The Gurdon Institute 35

HANSONG MA

Mitochondrial DNA transmission and maintenance wild type mtDNA mutant mtDNA

maternal How mitochondrial genomes are transmitted and maintained. In inheritance addition to the nuclear genome, all animals have another genome packed inside the mitochondrion called mtDNA. This maternally inherited genome encodes important proteins for energy production. During development and ageing, as mtDNA continues to replicate and turnover, mutations can occur to some of the copies. The subsequent prevalence of these mutants, which determines the progression and inheritance of the clinical abnormalities of mitochondrial disorders, depends on how they compete with the co-existing wild-type genomes for transmission. To date, over 50 mtDNA-linked disorders have been mtDNA described in humans. repair

We have developed genetic systems in Drosophila to study the rules governing the transmission of mtDNA mutations. By creating fruit flies carrying both functional and pathogenic mitochondrial genomes, we heteroplasmic reveal nuclear factors and mtDNA sequence polymorphisms that bias transmission the transmission of one genome over the other. We also study repair mechanisms that safeguard the integrity of mtDNA during development and ageing. The maternally transmitted is a Selected publications: mitochondrial DNA (mtDNA) multi-copy genome that shows complex Chiang A et al. (2019) A Genome-wide screen reveals that reducing transmission patterns during developing mitochondrial DNA polymerase can promote elimination of deleterious and aging, and between generations mitochondrial mutations. Curr Biol 29: 4330-36. due to relaxed replication, random Klucnika A & Ma H (2019) A battle for transmission: the selfish and segregation, and selection that favours corporative animal mitochondrial genomes. Open Biol 9: 180267. the transmission of one genome over Co-workers: Ason Chiang, Ivy Ma H & O’Farrell PH (2016) Selfish drive can trump function when animal another in the pool. In addition to Di, Beitong Gao, Jan Jezek, mitochondrial genomes compete. Nat Genet 48: 798–802. mitochondrial diseases caused by Anna Klucnika, Andy Li, Eleanor accumulation of a particular mutant, McCartney, Matthew McCormack, random mtDNA mutations have been Kathy Oswald, Sumaera Rathore, Ziming Wang shown to increase with age, contributing to mitochondrial dysfunction and various age-related conditions. 36 Group leaders The Gurdon Institute 37

ERIC MISKA Non-coding RNA and genome dynamics

What does non-coding RNA do in development and disease? Most of the RNA transcribed from the DNA in our genome is not 5′CS translated into protein but instead has direct functions in regulating biological processes. This paradigm shift in nucleic acid biology has 5′ been supported by technical advances in high-throughput sequencing, miR-21 molecular genetics and computational biology, which can be combined with more traditional biochemical analyses.

Many species and roles of non-coding RNA have been identified. Our goal is to understand how non-coding RNAs regulate development, physiology and disease. We are exploring microRNA in the pathology of cancer and other diseases, RNA interference in viral immunity, Piwi- interacting RNA in germline development and genome integrity, and endogenous small interfering RNA in epigenetic inheritance – where 5′ we predict a big impact in understanding human health. Our model 5′CS V organisms are the nematode worm, the cichlid fishes of the Rift Lakes 3′CS N of East Africa, mouse, and human cell culture. More recently we have M L developed a technology to assess RNA structure and RNA–RNA interactions in living systems. We used this to uncover unexpected 3′ biology for the Zika virus, and key regulatory mechanisms for SARS- 5′CS CoV-2. 5′

Selected publications: Ziv O et al. (2020) The Short- and Long-Range RNA–RNA Interactome of Harry Baird, Sarah Buddle, SARS-CoV-2. 80: 1067–1077.e5. Co-workers: Mol Cell The Zika virus genomic structure Nicholas Burton, Alexandra Dallaire, Maori E et al. (2019) A Secreted RNA Binding Protein Forms RNA-Stabilizing Benjamin Fisher, Giulia Furlan, David inside human cells Granules in the Honeybee Royal Jelly. 74: 598-608.e6. Jordan, Tsveta Kamenova, Joanna Mol Cell The Zika virus genome adopts Kosalka, Lisa Lampersberger, Miranda Ziv O et al. (2018) COMRADES determines in vivo RNA structures and alternating structures as the 5' Landgraf, Bethan Manley, Ragini Medhi, interactions. 15: 785–788. Narendra Meena, Harris Papadopoulou, Nat Methods cyclization sequence (CS) participates Jon Price, Audrey Putman, Fu Xiang in interaction with host microRNA Quah, Navin Brian Ramakrishna, Cristian miR-21 (top), capsid translation Riccio, Marc Ridyard, Miguel Vasconcelos (right), and genome cyclization (left). Almeida, Gregoire Vernaz, Archana Yerra, Chengwei (Ulrika) Yuan, Omer Ziv 38 Group leaders

EMMA RAWLINS Stem and progenitor cells in the mammalian lung

How do stem cells build and maintain the lung? The complicated three-dimensional structure of our lungs is essential for respiration and host defence. Building this structure relies on the correct sequence of division and differentiation events by lung progenitor cells, which also maintain the slowly turning-over airway epithelium in the adult. How is the production of different cell types controlled in embryonic development and adult maintenance? We apply mouse genetics, live imaging, single-cell molecular analysis and mathematical modelling to understand lung stem cells, with a longer-term aim of directing endogenous lung cells to repair, or regenerate, diseased tissue.

In the adult lung we focus on the cellular mechanisms that maintain stem cell quiescence at steady-state, but allow a rapid repair response when needed. In the embryonic lung we study a population of multipotent progenitors that undergo steroid-induced changes in competence during development. In the embryo, we have recently switched our focus to normal human lung development, primarily using an organoid system that we developed. We combine the analysis of fresh human embryonic tissue with gene-targeting in the organoids, to determine the molecular and cellular mechanisms of normal human lung development. This will provide insights into conditions related to premature birth and into the possibility of therapeutic lung regeneration.

Selected publications: Nikolic´ M et al. (2018) Human lung development: recent progress and new challenges. Development 145: dev163485. Co-workers: Ana Lucia Cabriales Nikolic´ M et al. (2017) Human embryonic lung epithelial tips are multipotent Torrijos, Ziqi Dong, Tessa Hughes, progenitors that can be expanded in vitro as long-term self-renewing Quitz Jeng, Florence Leroy, Kyungtae organoids. 6: e26575. Lim, Shuyu Liu, Vishal Menon, Ziming Elife Shao, Vanesa Sokleva, Dawei Sun Balasooriya GI et al. (2016) An FGFR1-SPRY2 Signaling Axis Limits Basal Cell How does the lung build itself? Proliferation in the Steady-State Airway Epithelium. Dev Cell 37: 85–97. In this 17-weeks-gestation human embryonic lung, the differentiating airway epithelium has been stained to visualise mRNA. Differentiating secretory cells (cyan) and ciliated cells (red) are visible. Cell nuclei in blue. (Credit: Dr Kyungtae Lim.) 40 Group leaders

DANIEL ST JOHNSTON apical domain secretion Polarising epithelial cells and body axes apical

How do cells know ‘up’ from ‘down’? Most cells in the body perform different functions at opposite sides of the cell. This cell polarity is lateral essential in development, for example: in determining the head-to-tail axis of many animals, for cell migration and for asymmetric stem-cell divisions. Furthermore, loss of polarity is a hallmark of tumour cells and is thought to contribute to tissue invasion and metastasis. Our work forming sheets basal focuses on epithelia, the sheets of polarised cells that form barriers that create a between compartments and make up most of our organs and tissues. barrier We study the factors that mark different sides of epithelial cells and how these organise the internal cell architecture, using the Drosophila loss of polarity intestine and the follicle cell epithelium as models. in cancer

We have recently discovered that the gut epithelium polarises by a fundamentally different mechanism from other fly epithelia, and is forming tubes much more similar to mammalian epithelia. We are now identifying new polarity factors in the fly gut and are testing whether these play similar roles in mouse intestinal organoids. We are also using live microscopy to visualise polarised secretion in epithelial cells, and quantitative super- resolution microscopy to examine the clustering and co-localisation of polarity proteins.

Selected publications: Lovegrove H et al. (2019) The role of integrins in Drosophila egg chamber morphogenesis. Development 146: dev182774 Fic W et al. (2019) Drosophila IMP regulates Kuzbanian to control the timing of Notch signalling in the follicle cells. 146: dev168963. Development The special properties of epithelia Co-workers: Edward Allgeyer, Jia Chen, Chen J et al. (2018) An alternative mode of epithelial polarity in the Drosophila A drawing showing how epithelial cells stick together to form epithelial sheets, with their free apical surfaces Jin Mei Cheng, Helene Doerflinger, midgut. PLoS Biol 16: e3000041. Weronika Fic, Xiao Li He, Nathan facing towards the outside or the lumen of an epithelial tube or gland. The lateral junctions (yellow) create a Hervieux, Florence Leroy, Dmitry barrier between cells so that fluids, solutes and pathogens cannot leak across the epithelium. Most cancers Nashchekin, John Overton, Amandine arise from epithelial tissues and are characterised by a loss of apical–basal polarity (red cells). Palandri, Jenny Richens, George Sirinakis, Mihoko Tame, Joseph Jose Thottachery, Helen Zenner, Xixi Zhu 42 Group leaders The Gurdon Institute 43

BEN SIMONS Mechanisms of stem cell fate in tissue development, maintenance and disease

How do stem and progenitor cells regulate their fate behaviour to specify and maintain tissues? During development, cell proliferation and differentiation must be coordinated with collective cell movements to specify organs of the correct size, pattern and composition. In the adult, stem cells must regulate a precise balance between proliferation and differentiation to maintain tissue homeostasis.

To address the mechanisms that regulate stem and progenitor cell fate, we combine cell lineage-tracing approaches and single-cell gene expression profiling with concepts and methods from statistical physics and mathematics. Applied to epithelial tissues, we have shown how common principles of self-organisation and emergence provide predictive insights into the cellular mechanisms that regulate tissue development, maintenance and repair. As well as questioning the nature of stem cell identity and function, these studies emphasize the role of cell fate stochasticity and state flexibility, and establish a quantitative platform to investigate pathways leading to cancer initiation and progression.

Selected publications: Han S et al. (2019) Defining the identity and dynamics of adult gastric isthmus stem cells. Cell Stem Cell 25: 342–356. Kitadate Y et al. (2019) Competition for mitogens regulates spermatogenic stem cell homeostasis in an open niche. Cell Stem Cell 24: 79–92. Hannezo E et al. (2017) A unifying theory of branching morphogenesis. Cell 171: 242–255. Co-workers: Ignacio Bordeu, Lemonia Cell lineage tracing in the stomach corpus Chatzeli, Catherine Dabrowska, Frances England, Adrien Hallou, Seungmin Genetic lineage tracing using a multicolour confetti reporter system reveals the compartmentalisation of the Han, Daniel Kunz, Jamie McGinn, Kathy mouse stomach corpus gland. (Credit: Juergen Fink and Seungmin Han.) Oswald, Bart Theeuwes, Yanbo Yin, Min Kyu Yum 44 Group leaders The Gurdon Institute 45

AZIM SURANI Germ cell development in vivo E6 E14 E16 E23 E29 week 7-10 (week 4) (week 5) The human germline epiblast

What makes a germline cell? We study primordial germ cells (PGCs), precursors to eggs and sperm, in the early embryo. We have established principles of early human development with a focus on human PGC (hPGC) specification. A unique epigenetic resetting follows in the germline after hPGC specification. Our work shows genital ridge that SOX17 is the key regulator of human, but not mouse, germ cell primordial fate. By developing in vitro models, and with authentic hPGCs from germ cells human embryos, we have also established how pluripotent stem cells gain competence for germ cell and somatic fates in human. These findings are important for studies on human pluripotent stem cells adults and regenerative medicine. The inheritance of genetic and epigenetic information from the germline through the totipotent state affects Reconstitution of cell fate transition in vitro human development and disease for generations. BMP Whereas SOX17–BLIMP1 apparently initiate the epigenetic programme WNT/BMP/ in early human germline, BLIMP1–PRDM14 play a similar role in mouse Activin germline, resulting in the comprehensive erasure of DNA methylation mesoderm (except for some resistant loci), X-reactivation and imprints erasure, Activin followed by re-establishment of sperm- and oocyte-specific imprints. conventional human pre-mesendoderm mesendoderm Defects in these gamete-specific imprints lead to a variety of human pluripotent stem cells BMP disease syndromes. We have also examined mitochondrial DNA SOX17 (mtDNA) in PGCs, showing evidence for selection against mitochondria that harbour mutations. This mechanism is imperfect and can account SOX17 for inherited mtDNA disorders.

Selected publications: Sybirna A et al. (2020) A critical role of PRDM14 in human primordial germ Co-workers: João Alves Lopes, cell fate revealed by inducible degrons. Nat Commun 11: 1282. primordial germ cells definitive endoderm Aracely Castillo, Lynn Froggett, Wolfram Gruhn, Mei Gu, Naoko Floros VI et al. (2018) Segregation of mitochondrial DNA heteroplasmy Irie, Sun Min Lee, Jitesh Neupane, through a developmental genetic bottleneck in human embryos. Nat Cell Marco Oechsner, So Shimamoto, Biol 20: 144– 151. What we know about primordial germ cell development Walfred Tang, Frederick Wong Kobayashi T et al. (2017) Principles of early human development and germ Primordial germ cells are the first cell type to be specified in vivo in early human development. We have cell program from conserved model systems. Nature 546: 416–420. developed a protocol using specific signalling molecules to generate primordial germ cell-like cellsin vitro Irie N et al. (2015) SOX17 Is a Critical Specifier of Human Primordial Germ from human pluripotent stem cells. We found that SOX17 is a critical determinant of human germ cell fate. Cell Fate. Cell 160: 253–268. 46 Group leaders The Gurdon Institute 47

IVA TCHASOVNIKAROVA Genetic interrogation of epigenetic pathways Left: A genome-wide CRISPR/Cas9 screen to identify genes required for transgene silencing. Six genes are required for epigenetic silencing of a How do changes in epigenetic pathways result in cancer? All repressed GFP reporter: the three HUSH complex DNA-templated processes occur in the context of chromatin, which is subunits TASOR, MPP8 and Periphilin; the H3K9 H3K9me3 comprised of DNA and histone proteins. Epigenetic modifications of methyltransferase SETDB1 and its binding partner DNA and histones are important regulators of transcription, DNA repair ATF7IP; and the chromatin remodeller MORC2. and replication. Disruption of epigenetic processes can therefore result

in malignant cellular transformation. Right: Mechanism of HUSH-mediated repression. The HUSH complex localises to genomic loci rich Gene1 Gene 2 The overarching goal of our research is to use novel genetic approaches in the repressive histone modification H3K9me3. to study epigenetic pathways and the mechanisms through which these Subsequent recruitment of the SETDB1/ ATF7IP processes are corrupted by disease-associated mutations in chromatin complex and MORC2 is required for further regulators. We aim to (1) understand the molecular mechanisms used H3K9me3 deposition and ATP-dependent HUSH chromatin compaction to instil epigenetic silencing. by chromatin regulators to exert their function in healthy human cells, TASOR and (2) examine how these mechanisms are altered in cancer. MPP8 We leverage high-throughput genetic technologies, such as CRISPR/ PPHLN1 Cas9 genetic screens, to discover novel factors involved in chromatin GFP pathways. This approach has led to the identification of HUSH, a H3K9me3 Co-worker: Lynn Froggett previously uncharacterised chromatin-modifying complex. In addition to HUSH deposition mediating position-effect variegation in human cells, the HUSH complex Gene 1 Gene 2 also plays key roles in the silencing of retro-elements and unintegrated retroviral DNA, and as a restriction factor for Human Immunodeficiency SETDB1 chromatin Virus. Therefore, a major focus of our research is achieving a mechanistic Periphilin compaction understanding of HUSH-mediated repression. In parallel, we are MORC2 SETDB1 TASOR ATF7IP developing novel genetic approaches that would allow us to interrogate ATF7IP chromatin other epigenetic pathways in an analogous manner. compaction H3K9me3 MORC2 deposition Selected publications: enriched in selected cells MPP8 Tchasovnikarova IA et al. (2015) Epigenetic silencing by the HUSH complex GFP mediates position-effect variegation in human cells. Science 348: 1481–1485. Tchasovnikarova IA et al. (2017) Hyperactivation of HUSH complex function all mutated genes Gene 1 Gene 2 by Charcot-Marie-Tooth disease mutation in MORC2. Nat Genet 49: 1035–1044. Timms RT et al. (2019) Differential Viral Accessibility (DIVA) identifies alterations in chromatin architecture through large-scale mapping of lentiviral integration sites. Nat Protoc 14: 153–170. 48 Group leaders The Gurdon Institute 49

FENGZHU XIONG Tissue morphogenesis by mechanics and cell dynamics

What forces drive tissue morphogenesis? Embryos are made of soft materials consisting of cells with limited mechanical capacities, yet they develop in a robust and coordinated manner and produce large-scale deformations (morphogenesis). We are interested in the ways in which developing tissues produce and respond to mechanical forces in order to achieve the correct shape and pattern. This knowledge is useful for understanding complex birth defects and engineering stem or reprogrammed cells into tissues, as well as interpreting the changes in diseased tissues such as tumours.

We use early avian embryos as a model system. The large size and accessibility of these embryos allow us to image cell and tissue dynamics, perform molecular genetic perturbations, and deploy novel mechanical tools such as soft gels and cantilevers to measure and apply forces. By integrating cell and tissue dynamics, we found that the paraxial mesoderm and axial tissues coordinate their elongation through mechanical feedback. We are currently investigating if the identified forces are also important for the straightness (bilateral symmetry) of the tissues and the folding of the neural tube.

Selected publications: Oginuma M et al. (2020) Intracellular pH controls WNT downstream of glycolysis in amniote embryos. Nature 584: 98–101. Naturally occurring twin chick embryo Xiong F et al. (2020) Mechanical coupling coordinates the co-elongation of Bright-field image of a rare pair of well-formed axial and paraxial tissues in avian embryos. 55: 354–366. Dev Cell separate embryos sharing one egg. The embryos Mongera A et al. (2019) Mechanics of Anteroposterior Axis Formation in show a head-to-head alignment. Body axis and Co-workers: Christopher Chan, Ana Vertebrates. Annu Rev Cell Dev Biol 35: 259–283 somites are visible. (Credit: Daniele Kunz) Hernandez Rodriguez, Daniele Kunz, Yisha Lan, Lauren Moon, Kathy Oswald, Melinda Van Kerckvoorde, Anfu Wang, Melissa Yuan 50 Group leaders The Gurdon Institute 51

PHILIP ZEGERMAN

The regulation of DNA replication initiation in eukaryotes origin of replication

How is DNA replication controlled? A fundamental requirement for all life on earth is that an exact copy of the entire genome must be made before cell division. DNA replication is therefore tightly regulated because failures in this process cause genomic instability, which is a hallmark of many diseases, most notably cancers. In addition, inhibition of DNA replication is the primary mode of action of many anti-tumour therapies. Therefore, investigating DNA replication control two fully replicated DNA is important for finding new ways to diagnose and treat cancers. The strands ready for cell division evolutionary conservation of DNA replication mechanisms allows us to study this process in multiple systems, facilitating the translation of findings to humans.

We have shown that the levels of several key replication factors are critical to control the rate of genome duplication, not only in the single-celled organism, budding yeast, but also during vertebrate development in frog embryos. Our studies demonstrate that regulation of the levels of these factors is vital not only for normal cell division, but also for regulating the rate of cell proliferation in animal tissue. This has important implications for the deregulation of cell proliferation, which occurs in cancers. incomplete replication replication Selected publications: initiation happens Morafraile EC et al. (2019) Checkpoint inhibition of origin firing prevents more than once DNA topological stress. Genes Dev 33: 1539–1554. before cell division Can G et al. (2019) Helicase Subunit Cdc45 Targets the Checkpoint Kinase mutation Rad53 to Both Replication Initiation and Elongation Complexes after Fork Stalling. Mol Cell 73: p562–573.e3 Co-workers: Andreas Hadjicharalambous, Fiona Jenkinson, Collart C et al. (2017) Chk1 Inhibition of the Replication Factor Drf1 Studying life’s central process Mark Johnson, Florence Leroy, Ivan Guarantees Cell-Cycle Elongation at the Xenopus laevis Mid-blastula Phanada, Miguel Santos Regulation of replication initiation is critical for normal cell division. Transition. Dev Cell 42: 82–96. Collart C et al. (2013) Titration of four replication factors is essential for the Xenopus laevis midblastula transition. Science 341: 893–896. 52 Associate group leaders The Gurdon Institute 53

KDM MARTIN HOWARD Active Building simple predictive models of complex biological processes Pol II Pol II

How are cellular memory states switched and maintained? Our PRC2 PRC2 group combines simple, predictive mathematical modelling with long- lasting experimental collaborations, to dissect biological mechanisms Repressed too complex to unravel by experiments alone. In many cases we are able to rationalise complex biological dynamics into simple underlying mechanisms, with few components and interactions. Our approach is highly interdisciplinary and relies heavily on the techniques of statistical physics and applied mathematics, as well as on close collaboration with experimental groups. This truly interdisciplinary approach allows Trans-regulators me0 me1 me2 me3 us to get to the heart of biological mechanisms more speedily.

At present the main focus of the group is epigenetic dynamics, probing how epigenetic memory states are set up and then stably maintained. In this context, we work with histone modification memory systems, Transcription as well as on DNA methylation, collaborating with experimentalists in systems ranging from plants to mammalian stem cells. A particular 1 1 focus has been the Polycomb epigenetic system, where we have proposed an all-or-nothing epigenetic switching mechanism, with me0 me0 epigenetic gene silencing directly antagonised by transcription. Overall, as epigenetic systems are central to health, understanding 0 0 how they work at a fundamental level is of vital importance. 1 1 Modification level Modification level Selected publications: me3 me3 Zhao Y et al. (2020) Temperature-dependent growth contributes to long- 0 0 term cold sensing. Nature 583: 825-829. 0 2 4 6 8 0 2 4 6 8 Yang H et al. (2017) Distinct phases of Polycomb silencing to hold epigenetic Time (cell cycles) Time (cell cycles) memory of cold in Arabidopsis. Science 357: 1142-1145. Berry S et al. (2017) Slow chromatin dynamics allow polycomb target genes to Modelling Polycomb epigenetic dynamics filter fluctuations in transcription factor activity. 4: 445-457.e8. Cell Systems Top: schematic of chromatin state in active (upper) and repressed (lower) state. KDM: histone demethylase; Pol II: RNA Polymerase II; PRC2: Polycomb Repressive Complex 2; orange hexagons: histone H3K27 di- and tri- methylation. Middle: key ingredients of a mathematical model for Polycomb dynamics; me0/1/2/3: methylation state of H3K27. Bottom: simulation of repressed state (high H3K27me3) (left) and of repressed state switching to an active state (right), both periodically perturbed by DNA replication. (Image credit: Dr Scott Berry). 54 Associate group leaders The Gurdon Institute 55

JOHN PERRY Analysing genotypes and phenotypes in human populations phenotype Using human genetics to understand disease mechanisms

What are the biological mechanisms that link patterns of growth and reproductive ageing to later life disease? Epidemiological phenotype genotype studies have long linked patterns of early-life growth and reproductive ageing to later life diseases, yet the biological mechanisms Identifying genetic determinants of health and disease underpinning these associations remain unclear. For example, what are the pathways that link variation in onset of puberty to risk of type 2 diabetes and cancer decades later? To explore this, we use large-scale human population studies to identify genetic variants that influence risk of disease or contribute to variation in quantitative traits. Through integration with transcriptomic and proteomic datasets we can then prioritise genes and pathways for evaluation with experimental 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X collaborators using animal and cellular models. chromosome

My research is primarily based at the MRC Epidemiology Unit where Understanding gene function and biological mechanisms I co-lead an MRC-funded programme with Professor Ken Ong. My Associate position at the Gurdon Institute focusses on one of the key biological mechanisms emerging from our population-based functional models research: DNA damage response (DDR). Although often considered in the context of cancer susceptibility, it is now clear that DDR processes influence other complex diseases and traits. For example, transcriptome epigenome our human genetics work has highlighted DDR as the major pathway intervention/ therapeutics Co-workers: Ken Ong, Felix Day, governing reproductive ageing and fertility in women. We aim to better Hana Lango Allen, Yajie Zhao and understand these processes, when they act over the life-course and how Stasa Stankovic they might be modified to preserve fertility and prevent disease. in vivo in vitro

Selected publications: Ruth KS et al. (2020) Using human genetics to understand the disease impacts Overview of process to identify disease- and trait-associated proteome metabolome alleles, genes and biological pathways using large-scale human of testosterone in men and women. Nat Med 26: 252–258. population studies. Genetic variation is measured genome-wide Thompson DJ et al. (2019) Genetic predisposition to mosaic Y chromosome in populations of research participants. Individual genetic variants loss in blood. 575: 652–657. Nature associated with diseases and traits can then be identified through Perry JRB et al. (2014) Parent-of-origin-specific allelic associations among 106 computational approaches, linked to gene function through genomic loci for age at menarche. Nature 514: 92–97. the integration of ‘omics’ resources and further evaluated in downstream experimental models. 56 Facilities The Gurdon Institute 57 Facilities

Media/glasswashing service Microscopy and image analysis Next-generation sequencing and IT/computing The media team provide quality-controlled buffers, The team run the technical support for a wide bioinformatics The computing team provides flexible and high- growth media, worm plates, bacterial plates, range of the latest imaging technologies, as well On-site sequencing allows researchers to access quality IT infrastructure, services and support fly vials and bottles, and standard and custom as providing training, research contributions and results with a quick turnaround. Bioinformatics for all research and administrative computing solutions. They collect and wash used glassware custom software development. expertise is provided by core posts as well as by activities within the Institute. We maintain high and provide sterile supplies. research-group-based posts. A High Performance performance, high capacity and high bandwidth Researchers have access to confocal, light-sheet Computer cluster offers researchers the capability systems that are secure, resilient and highly Typical annual production of media includes and super-resolution (STORM, PALM, STED, SIM) to process sequencing data in-house. These available, ensuring the efficient movement, secure 400,000 vials and bottles of fly food; 300,000 microscopes. We also have a cell-sorting core. services are backed up by locally available courses storage, and future accessibility and re-use of a nematode worm plates; and over 100 different in a variety of programming and analysis tools. very large volume of research data. We also strive recipes for buffers, media and solutions. The duo building our new super-resolution microscopes describe their work in a video in our to provide the very best levels of user support and The sequencing service is featured in a video in Find out more about the media team in the video YouTube series: ‘A Year in Institute Life’. engagement, responding rapidly to both problems our YouTube series: ‘A Year in Institute Life’. for our YouTube series: ‘A Year in Institute Life’. and opportunities for new services. 58 Support staff The Gurdon Institute 59

Miguel Leon Salvador Tracy Mitchell Support staff Nathy Villalobos Martinez MA

Sylviane Moss PhD Natalie Walls BSc Safety and Compliance Manager Public Engagement Coordinator Imaging Combined building & Dermot Nolan Alexander Sossick BSc Receptionist Head of Microscopy and services group Scientific Facilities Co-ordinator, Alan Rix Samantha Wilson BSc Laser Safety Officer Receptionist Building Services Manager Richard Butler PhD Clive Bennett Daniel Sargent Research Associate (Imaging) Accounts/ Purchasing/ HR Administrator Custodian Administration Stores Nicola Lawrence PhD Katharine Bennett Victoria Stubbs PhD Microscopy Associate/ Deputy Ian Fleming Bruce Daniels LLB DipLP BTh Shared Facilities Manager Custodian Administration and Operations Computing/ IT Head of Imaging, Laser Safety Stores/ Purchasing Manager Officer Paul Turrell Manager Alastair Downie Simon Aldis Custodian Computer Systems Manager Purchasing/ Accounts Assistant Jane Course Regimantas Vysniauskas Finance Manager Nigel Smith David Cooper Senior Building Services Computer Associate Stores Technician Jayne Fisher Technician Finance/ Accounts Assistant Peter Williamson BSc Andrew Vincent Computer Associate Senior Stores Technician Diane Foster Technical facilities Deputy Administration and Polly Attlesey RAnTech MIAT Operations Manager, Principal Bioinformatics Super-resolution Facilities Manager Technician Communications/ Public microscopy Charles Bradshaw PhD Media/ Glasswashing Therese Jones-Green BSc Emma Gant BA PGCert engagement Bioinformatician George Sirinakis PhD Manager of Aquatic Services Research Grants/ HR Juanita Baker-Hay Wellcome Senior Research Coordinator Hélène Doerflinger PhD Media/ Glasswashing Manager Public Engagement Manager Sequencing Associate Zest catering Lisa Baker Iolanda Guerra Edward Allgeyer PhD Health and Safety Adviser Claire O’Brien PhD Kevin (Kay) Harnish MSc Amanda Harris Information and Wellcome Research Assistant Laura Carlton Wellcome Senior Research Associate Lynda Lockey Communications Officer (Sequencing Facility) Vincent Dams Melissa Plowden Roberts Office Manager Sandra Human 60 People in 2019 The Gurdon Institute 61

Seminars, events and publications in 2019/2020 62 Seminars The Gurdon Institute 63 Seminars External events

The Gurdon Institute Seminar Curie, Paris, France. Human development: the “distal pinning” 14 Oct ’19: Artist Caroline Walker Series brings high-profile Regulator of TElomere Length mechanism was commissioned by Cambridge international scientists in front of Helicase 1 (RTEL1) couples nuclear University Library to capture images an audience drawn from across envelope stability and functions to 30 June 2020 of women working in the lab at the the University biological sciences genome replication Fabian Theis, Institute of Gurdon Institute. After shadowing departments. Our speakers were: Computational Biology, Helmholtz researchers in the Rawlins lab and 31 October 2019 Zentrum, Munich, Germany. taking photographs, Caroline 5 March 2019 Hiten Madhani, University of Model-based explanation of cellular created a huge oil painting for the , The University California, San Francisco, USA. response. Live webinar hosted Yunsun Nam June ’19: The Milner Therapeutics library’s entrance hall, on view to Sept ’20: Adrestia Therapeutics, of Texas Southwestern Medical Epigenetic memory over geological by the Gurdon Institute Postdoc Institute team officially moved the public as part of the exhibition the latest biotech company to spin Center, USA. Chemical regulation of timescales Association out of their incubation space at 'The Rising Tide: Women at out from the Jackson lab, moved functional RNAs the Gurdon Institute and into . [You can see details out of the Institute’s temporary 26 November 2019 27 July 2020 Cambridge' their new premises in the Jeffrey from the preparatory oil sketches incubation space and into new 30 April 2019 , MRC Laboratory of , Max-Planck Lori Passmore Nadine Vastenhouw Cheah Biomedical Centre on the throughout this prospectus.] premises on the Babraham Research , Hospital for Sick Molecular Biology, Cambridge, UK. Institute of Molecular Cell Biology & Janet Rossant Cambridge Biomedical Campus, Campus. The company’s Disease Children, University of Toronto, Mechanistic insights into the mRNA Genetics, Dresden, Germany. Firing with a goodbye tea for colleagues. Sept ‘19: Over 2000 cyclists from Rebalancing Platform uses synthetic Canada. The Anne McLaren Lecture: poly(A) tail machinery and DNA up the genome. Live webinar hosted 184 organisations across Greater viability to identify phenotypic and The blastocyst and its stem cells; repair by the Gurdon Institute Postdoc Cambridge took part in the Global molecular imbalances of disease as from mouse to human relevance Association Bike Challenge and clocked 28 January 2020 the basis of novel drug discovery. up 290,466 miles during 16 May 2019 , Rockefeller University, 13 October 2020 Cycle In Dec ’20 GlaxoSmithKline and Elaine Fuchs - and many of those , Cornell New York, USA. , Anderson Center September Ahren Innovation Capital co-led a Cédric Feschotte Titia de Lange were logged by Gurdon Institute University, Ithaca, New York, USA. Stem Cells: It’s All About the for Cancer Research, Rockefeller substantial Series A investment in staff. The Institute bagged 2nd place Transposable elements as Neighborhood University, New York, USA. The Anne Adrestia. 22 Aug and 20 Sept ’19: in the league tables for companies catalysts of cellular innovation McLaren Lecture: How CST protects East of Catherine Rowett in our size range. Cycle September 28 January 2020 telomeres and double-strand England MEPs (UK Green Party) and Barbara is run by cycling organisation Love Seminars for the local 21 May 2019 Eduardo Moreno, Champalimaud breaks. Live webinar Gibson (Liberal Democrat) visited to Ride. academic community Philip W Ingham, Lee Kong Chian Centre for the Unknown, Lisbon, Beyond the Gurdon Institute the Institute to learn about who School of Medicine, Nanyang Portugal. Cell competition during 17 November 2020 seminars, our members organise, we are and what we do. Each was Jan ’20: The newly launched Technological University Singapore development and disease Martin Howard, John Innes Centre, host and support several other on a fact-finding mission to hear Cambridge Centre for Physical & Imperial College London. Spatio- Hosted by the Gurdon Institute PhD Norwich. Mechanistic basis of series: Developmental Biology from group leaders and young Biology aims to support and facilitate temporal dynamics of cell fate Society epigenetic switching and memory. Seminars, Cambridge RNA researchers about the impact of multidisciplinary collaborations across specification and differentiation in the Live webinar Club, Cambridge Epigenetics 04 February 2020 the Brexit vote and continuing the University of Cambridge. Gurdon zebrafish embryo Club, Cambridge Fly Meeting, , Weizmann Institute uncertainty about the future, on Institute Group Leader Professor Ben Naama Barkai Cambridge 3Rs (replication, repair 29 October 2019 of Science, Rehovot, Israel. people's lives, career decisions and Simons is one of the main leaders of and recombination), Life Science , Institut Robustness and scaling in early the UK science base. the project. Arturo Londoño-Vallejo Masterclasses and Worm Club. 64 Events The Gurdon Institute 65 Institute events

We hold regular social and sports students to talk to each other, ask activities, celebrations and specific any questions, and raise concerns events organised by our postdoc - basically get to know each other. and PhD student associations. Here We plan to hold events throughout is a selection: the year.”

17 Jan '19: A Fizz & Food party to 3 July '19: To celebrate LGBT STEM celebrate Daniel St Johnston's day we held a seminar by special 10 years as Director. Several past guest Duncan Astle (Programme Group Leaders and our previous Leader, MRC Cognition and Institute Administrator attended. Brain Sciences Unit & member Speeches were followed by an of Pride in STEM) talking about inspired song specially written his research: Altering developing and sung by Andrew Plygawko (St neurophysiology with training. Johnston lab PhD student). 7 July '19: Our first Family Day, Feb '19: Launch of Climbing Club, on a Sunday, featuring a walk, activities: Talks from all our group organised by Miguel Leon Salvador games and a picnic in Grantchester leaders, guest speaker Prof Anna from the Media team. Club sessions Meadows. Organised by Gurdon Philpott (Stem Cell Institute and packet recycling scheme); Ann 6 Mar ’20: GIPA Carnival evening during the pandemic. For enabling run on two evenings per week at the Institute Postdoc Association (GIPA) Cartwright Good Citizen Award (the lockdown and reopening: Fabian Head of School of the Biological July ’20: The PE team supported local sports hall. and the Wellbeing, Equality and Sciences), 'treasure hunt' games, Maintenance Team for their unfailing Braukmann, Chris Carnie, Andrea one session of the Secret School Diversity (WED) Committee. poster session and plenty of fun on brilliant work); Martin Evans Award Frapporti and Roopali Pradhan. June '19: Launch of the for Curious Children. ‘Invisible Gurdon the dance floor after dinner. for the greatest contribution to For handmade masks: Carmen Institute PhD Society. Vanesa 12 July '19: Our Gratitude Festival Institute social life (Miguel Salvador, Nature’ took place in the sunny Calabrese. For bringing us through Sokleva (Rawlins lab), the new was the perfect moment to say Prizes announced at the Retreat: for organising Climbing Club). outdoors with social distancing, and lockdown 1.0 and safely back to President, says: "We want it to be Goodbye and a big Thank You to Three best posters (Rue Jones- featured the popular Zoom boxes work: Di Foster, Sylviane Moss, a friendly and safe space for PhD Suzanne (retiring long-serving HR Green, Leia Judge & Israel 25 Oct '19: Halloween Happy Hour that create a microscope out of a Katherine Wallington and Arianna & Grants Manager) and to the Salguero); Image competition by the Jackson lab. The undisputed mobile phone. Children scavenged Pezzuolo. Huch and Livesey labs (moving to (Andy Li); Video competition winner of the pumpkin carving for specimens and learnt about Dresden and London, respectively). (Chufan Xu); Public Engagement competition was David Jordan magnification. The Public Engagement Activities included face painting, Champion (Bernhard Strauss for (Miska lab). Champion Award 2020 goes to 1 & 2 Oct ’20: virtual Institute tie-dyeing, a bouncy castle and many years running workshops Edward Allgeyer, for creating a 22 Nov '19: GIPA Pub Quiz Happy Retreat. We had two half days to science tattoos. for sixth formers, supporting work workshop enabling students to Hour. hear the talks from researchers and experience students, and taking part build simple microscopes for the 3 & 4 Oct '19: Institute Retreat core teams, and an evening session CAST microscopy challenge, run in in numerous external events); Kathy 10 and 13 Dec '19: Children’s and at Dunston Hall in Norfolk (see p. for the ‘treasure hunt/ quiz’. Awards collaboration with our Imaging team Hilton Energy and Environment Adults’ (the latter 76). The schedule had all the usual Christmas parties went to those making exceptional and Zeiss. Champion (Kate Dry, for crisp with Cartoon Character fancy dress). contributions to the Institute Credit: Claudia Stocker 66 Publications in 2019 The Gurdon Institute 67

Beurton F, Stempor P, Caron M, Appert A, Dong Y, Fic W, Faria C, St Johnston D (2019) IMP regulates Chen RA-J, Cluet D, Couté Y, Herbette M, Huang Kuzbanian to control the timing of Notch signalling N, Polveche H, Spichty M, Bedet C, Ahringer J, in Drosophila follicle cells. Development 146: Publications in 2019 Palladino F (2019) Physical and functional interaction dev168963. DOI: 10.1242/dev.168963. between SET1/COMPASS complex component Gallop JL (2019) Filopodia and their links with CFP-1 and a Sin3S HDAC complex in C. elegans. membrane traffic and cell adhesion.Semin Cell Dev Nucleic Acids Res 47: 11164–11180. DOI: 10.1093/ Adashi EY, Cohen IG, Hanna JH, , Hayashi Aztekin C, Hiscock TW, Marioni JC, , Biol DOI: 10.1016/j.semcdb.2019.11.017. Surani AM Gurdon JB Simons nar/gkz880. K (2019) Stem Cell-Derived Human Gametes: The BD, Jullien J (2019) Identification of a regeneration- Gao X et al. (2019) Establishment of porcine and human Bezler A, Braukmann F, West SM, Duplan A, Conconi Public Engagement Imperative. Trends Mol Med 25: organizing cell in the Xenopus tail. Science 364: expanded potential stem cells. Nat Cell Biol 21: 165–167. DOI: 10.1016/j.molmed.2019.01.005. 653–658. DOI: 10.1126/science.aav9996. R, Schütz F, Gönczy P, Piano F, Gunsalus K, Miska 687–699. DOI: 10.1038/s41556-019-0333-2. [Surani lab] , Keller L (2019) Tissue- and sex-specific small Akay A, Jordan D, Navarro IC, Wrzesinski T, Ponting CP, Baker A-M, Cereser B, Melton S, Fletcher AG, EA RNAomes reveal sex differences in response to Gariboldi MI, Butler R, Best SM, Cameron RE (2019) , Haerty W (2019) Identification of functional Rodriguez-Justo M, Tadrous PJ, Humphries A, Elia Miska EA the environment. PLoS Genet 15: e1007905. DOI: Engineering vasculature: Architectural effects on long non-coding RNAs in C. elegans. BMC Biol 17: G, McDonald SAC, Wright NA, , Jansen Simons BD 10.1371/journal.pgen.1007905. microcapillary-like structure self-assembly. PLoS One 14. DOI: 10.1186/s12915-019-0635-7. M, Graham TA (2019) Quantification of Crypt and 14: e0210390. DOI: 10.1371/journal.pone.0210390. Stem Cell Evolution in the Normal and Neoplastic Chiang AC-Y, McCartney E, O’Farrell PH, Ma H (2019) Allen F, Crepaldi L, Alsinet C, Strong AJ, Kleshchevnikov [Imaging group] Human Colon. 27: 2524. DOI: 10.1016/j. A Genome-wide Screen Reveals that Reducing V, De Angeli P, Páleníková P, Khodak A, Kiselev V, Cell Rep celrep.2019.05.035. Mitochondrial DNA Polymerase Can Promote Gervais L, van den Beek M, Josserand M, Sallé J, Stefanutti Kosicki M, Bassett AR, Harding H, Galanty Y, Muñoz- Elimination of Deleterious Mitochondrial Mutations. M, Perdigoto CN, Skorski P, Mazouni K, Marshall OJ, Martínez F, Metzakopian E, , Parts L. (2019) Baker A-M, Gabbutt C, Williams MJ, Cereser B, Jawad Jackson SP Curr Biol 29: 4330–4336.e3. DOI: 10.1016/j. Brand AH, Schweisguth F, Bardin AJ (2019) Stem Predicting the mutations generated by repair of Cas9- N, Rodriguez-Justo M, Jansen M, Barnes CP, Simons cub.2019.10.060. Cell Proliferation Is Kept in Check by the Chromatin induced double-strand breaks. Nat Biotechnol 37: BD, McDonald SA, Graham TA, Wright NA (2019) Regulators Kismet/CHD7/CHD8 and Trr/MLL3/4. Dev Cornwell MJ, Thomson GJ, Coates J, Belotserkovskaya 64–72. DOI: 10.1038/nbt.4317. Crypt fusion as a homeostatic mechanism in the Cell 49: 556–573.e6. DOI: 10.1016/j.devcel.2019.04.033. human colon. 68: 1986–1993. DOI: 10.1136/ R, Waddell ID, , Galanty Y (2019) Small- Aloia L, McKie MA, Vernaz G, Cordero-Espinoza L, Gut Jackson SP gutjnl-2018-317540. Molecule Inhibition of UBE2T/FANCL-Mediated Guiu J, Hannezo E, Yui S, Demharter S, Ulyanchenko Aleksieva N, van den Ameele J, Antonica F, Font- Ubiquitylation in the Fanconi Anemia Pathway. S, Maimets M, Jørgensen A, Perlman S, Lundvall Cunill B, Raven A, Aiese Cigliano R, Belenguer G, Balmus G, Pilger D, Coates J, Demir M, Sczaniecka- ACS Chem Biol 14: 2148–2154. DOI: 10.1021/ L, Mamsen LS, Larsen A, Olesen RH, Andersen Mort RL, , Zernicka-Goetz M, Forbes SJ, Clift M, Barros AC, Woods M, Fu B, Yang F, Chen Brand AH acschembio.9b00570. CY, Thuesen LL, Hare KJ, Pers TH, Khodosevich K, , (2019) Epigenetic remodelling E, Ostermaier M, Stankovic T, Ponstingl H, Herzog Miska EA Huch M Simons BD, Jensen KB (2019) Tracing the origin of Elling U, Woods M, Forment JV, Fu B, Yang F, Ng BL, licences adult cholangiocytes for organoid formation M, Yusa K, Martinez FM, Durant ST, Galanty Y, Beli adult intestinal stem cells. Nature 570: 107–111. DOI: Vicente JR, Adams DJ, Doe B, , Penninger and liver regeneration. Nat Cell Biol 21: 1321–1333. P, Adams DJ, Bradley A, Metzakopian E, Forment Jackson SP 10.1038/s41586-019-1212-5. DOI: 10.1038/s41556-019-0402-6. JV, Jackson SP (2019) ATM orchestrates the DNA- JM, Balmus G (2019) Derivation and maintenance of damage response to counter toxic non-homologous mouse haploid embryonic stem cells. Nat Protoc 14: Hakes AE, Brand AH (2019) Neural stem cell dynamics: Andersen MS, Hannezo E, Ulyanchenko S, Estrach end-joining at broken replication forks. 1991–2014. DOI: 10.1038/s41596-019-0169-z. the development of brain tumours. Curr Opin Cell S, Antoku Y, Pisano S, Boonekamp KE, Sendrup S, Nat 10: 87. DOI: 10.1038/s41467-018-07729-2. Biol 60: 131–138. DOI: 10.1016/j.ceb.2019.06.001. Maimets M, Pedersen MT, Johansen JV, Clement DL, Commun Erdmann RS, Baguley SW, Richens JH, Wissner RF, Xi Z, Feral CC, Simons BD, Jensen KB (2019) Tracing the Beltran T, Barroso C, Birkle TY, Stevens L, Schwartz HT, Allgeyer ES, Zhong S, Thompson AD, Lowe N, Butler R, Han S, Fink J, Jörg DJ, Lee E, Yum MK, Chatzeli L, cellular dynamics of sebaceous gland development Sternberg PW, Fradin H, Gunsalus K, Piano F, Sharma Bewersdorf J, Rothman JE, St Johnston D, Schepartz Merker SR, Josserand M, Trendafilova T, Andersson- in normal and perturbed states. Nat Cell Biol 21: G, Cerrato C, Ahringer J, Martínez-Pérez E, Blaxter A, Toomre D (2019) Labeling Strategies Matter for Rolf A, Dabrowska C, Kim H, Naumann R, Lee J-H, 924–932. DOI: 10.1038/s41556-019-0362-x. M, Sarkies P (2019) Comparative Epigenomics Reveals Super-Resolution Microscopy: A Comparison between Sasaki N, Mort RL, Basak O, Clevers H, Stange DE, that RNA Polymerase II Pausing and Chromatin HaloTags and SNAP-tags. Cell Chem Biol 26: 584–592. Philpott A, Kim JK, Simons BD, Koo B-K (2019) Andrews TS, Hemberg M (2019) M3Drop: dropout- Domain Organization Control Nematode piRNA e6. DOI: 10.1016/j.chembiol.2019.01.003. Defining the Identity and Dynamics of Adult Gastric based feature selection for scRNASeq. Bioinformatics Biogenesis. 48: 793–810.e6. DOI: 10.1016/j. Isthmus Stem Cells. Cell Stem Cell 25: 342–356.e7. 35: 2865–2867. DOI: 10.1093/bioinformatics/bty1044. Dev Cell devcel.2018.12.026. DOI: 10.1016/j.stem.2019.07.008. 68 Publications in 2019 The Gurdon Institute 69

Hannezo E, Simons BD (2019) Multiscale dynamics of Kitadate Y, Jörg DJ, Tokue M, Maruyama A, Ichikawa Leger A, Amaral PP, Pandolfini L, Capitanchik Mongera A, Michaut A, Guillot C, Xiong F, Pourquié O branching morphogenesis. Curr Opin Cell Biol 60: R, Tsuchiya S, Segi-Nishida E, Nakagawa T, Uchida C, Capraro F, Barbieri I, Migliori V, Luscombe (2019) Mechanics of Anteroposterior Axis Formation 99–105. DOI: 10.1016/j.ceb.2019.04.008. A, Kimura-Yoshida C, Mizuno S, Sugiyama F, Azami NM, Enright AJ, Tzelepis K, Ule J, Fitzgerald T, in Vertebrates. Annu Rev Cell Dev Biol 35: 259–283. T, Ema M, Noda C, Kobayashi S, Matsuo I, Kanai Y, Birney E, Leonardi T, (2019) RNA DOI: 10.1146/annurev-cellbio-100818-125436. Hiscock TW (2019) Adapting machine-learning Kouzarides T Nagasawa T, Sugimoto Y, Takahashi S, , modifications detection by comparative Nanopore algorithms to design gene circuits. BMC Simons BD Morafraile EC, Hänni C, Allen G, Zeisner T, Clarke Yoshida S (2019) Competition for Mitogens Regulates direct RNA sequencing. bioRxiv DOI: https://doi. Bioinformatics 20: 214. DOI: 10.1186/s12859-019- C, Johnson MC, Santos MM, Carroll L, Minchell Spermatogenic Stem Cell Homeostasis in an Open org/10.1101/843136. 2788-3. [Simons lab] NE, Baxter J, Banks P, Lydall D, Zegerman P (2019) Niche. 24: 79–92.e6. DOI: 10.1016/j. Cell Stem Cell Li Z, Solomonidis EG, Meloni M, Taylor RS, Duffin R, Checkpoint inhibition of origin firing prevents DNA Hoffman M, Gillmor AH, Kunz DJ, Johnston MJ, Nikolic stem.2018.11.013. Dobie R, Magalhaes MS, Henderson BEP, Louwe topological stress. 33: 1539–1554. DOI: A, Narta K, Zarrei M, King J, Ellestad K, Dang NH, Genes Dev Klucnika A, (2019) A battle for transmission: PA, D’Amico G, Hodivala-Dilke KM, Shah AM, Mills 10.1101/gad.328682.119. Cavalli FMG, Kushida MM, Coutinho FJ, Zhu Y, Luu Ma H the cooperative and selfish animal mitochondrial NL, Simons BD, Gray GA, Henderson NC, Baker B, Ma Y, Mungall AJ, Moore R, Marra MA, Taylor MD, Otsuki L, Brand AH (2019) Dorsal-Ventral Differences genomes. 9: 180267. DOI: 10.1098/ AH, Brittan M (2019) Single-cell transcriptome Pugh TJ, Dirks PB, Strother D, Lafay-Cousin L, Resnick Open Biol in Neural Stem Cell Quiescence Are Induced by rsob.180267. analyses reveal novel targets modulating cardiac AC, Scherer S, Senger DL, Simons BD, Chan JA, p57KIP2/Dacapo. Dev Cell 49: 293–300.e3. DOI: neovascularization by resident endothelial cells Morrissy AS, Gallo M (2019) Intratumoral Genetic and Klucnika A, Ma H (2019) Mapping and editing animal 10.1016/j.devcel.2019.02.015. following myocardial infarction. 40: Functional Heterogeneity in Pediatric Glioblastoma. mitochondrial genomes: can we overcome the Eur Heart J 2507–2520. DOI: 10.1093/eurheartj/ehz305. Pacini CE, Bradshaw CR, Garrett NJ, Koziol MJ (2019) 79: 2111–2123. DOI: 10.1158/0008-5472. challenges? 375: Cancer Res Philos Trans R Soc Lond B Biol Sci Characteristics and homogeneity of N6-methylation CAN-18-3441. 20190187. DOI: 10.1098/rstb.2019.0187. Lovegrove HE, Bergstralh DT, (2019) St Johnston D in human genomes. Sci Rep 9: 5185. DOI: 10.1038/ The role of integrins in Drosophila egg chamber Howick VM, Russell AJC, Andrews T, Heaton H, Reid AJ, Krieger TG, Moran CM, Frangini A, Visser WE, s41598-019-41601-7. [Gurdon lab] morphogenesis. 146: dev182774. DOI: Natarajan K, Butungi H, Metcalf T, Verzier LH, Rayner Schoenmakers E, Muntoni F, Clark CA, Gadian Development 10.1242/dev.182774. Pandolfini L, Barbieri I, Bannister AJ, Hendrick A, Andrews JC, Berriman M, Herren JK, Billker O, D, Chong WK, Kuczynski A, Dattani M, Lyons G, Hemberg B, Webster N, Murat P, Mach P, Brandi R, Robson SC, , Talman AM, Lawniczak MKN (2019) The Malaria Efthymiadou A, Varga-Khadem F, , Maori E, Navarro IC, Boncristiani H, Seilly DJ, Rudolph M Simons BD Migliori V, Alendar A, d’Onofrio M, Balasubramanian S, Cell Atlas: Single parasite transcriptomes across Chatterjee K, Livesey FJ (2019) Mutations in thyroid KLM, Sapetschnig A, Lin C-C, Ladbury JE, Evans JD, Kouzarides T (2019) METTL1 Promotes let-7 MicroRNA the complete Plasmodium life cycle. Science 365: hormone receptor 1 cause premature neurogenesis Heeney JL, (2019) A Secreted RNA Binding α Miska EA Processing via m7G Methylation. Mol Cell 74: 1278– eaaw2619. DOI: 10.1126/science.aaw2619. and progenitor cell depletion in human cortical Protein Forms RNA-Stabilizing Granules in the 1290.e9. 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declines with age. Sci Rep 10: 10490. DOI: 10.1038/ (2020) Activin A and BMP4 Signaling Expands Potency Full staff lists for 2019 and 2020 can be found in the online supplement at www.gurdon.cam.ac.uk/about/prospectus s41598-020-66966-y. of Mouse Embryonic Stem Cells in Serum-Free Media. Stem Cell Rep 14: 241–255. DOI: 10.1016/j. Webber M, Jackson SP, Moon JC, Captur G (2020) International Scientific Advisory Board 2019 and 2020 stemcr.2020.01.004. Myocardial Fibrosis in Heart Failure: Anti-Fibrotic Therapies and the Role of Cardiovascular Magnetic Xiong F, Ma W, Bénazéraf B, Mahadevan L, Pourquié Professor Sir Adrian Bird (Chair) Professor Ken Zaret Resonance in Drug Trials. Cardiol Ther 9: 363–376. O (2020) Mechanical Coupling Coordinates the Wellcome Trust Centre for Cell Biology, University of Perelman School of Medicine, University of Pennsylvania DOI: 10.1007/s40119-020-00199-y. Co-elongation of Axial and Paraxial Tissues in Avian Edinburgh Embryos. 55: 354–366.E5. DOI: 10.1016/j. Dr Melanie Lee CBE Wein S, Andrews B, Sachsenberg T, Santos-Rosa H, Dev Cell devcel.2020.08.007. Professor Christine Mummery CEO of LifeArc Kohlbacher O, Kouzarides T, Garcia BA, Weisser H Leiden University Medical Center (2020) A computational platform for high-throughput Ziegler CGK, HCA Lung Biological Network et al. Professor Charles Swanton analysis of RNA sequences and modifications by mass (2020) SARS-CoV-2 Receptor ACE2 Is an Interferon- Professor Peter Rigby spectrometry. Nat Commun 11: 926. DOI: 10.1038/ Stimulated Gene in Human Airway Epithelial Cells The Francis Crick Institute, London s41467-020-14665-7. and Is Detected in Specific Cell Subsets across Professor Emeritus of Developmental Biology Dr Pierre Léopold Tissues. Cell 181: 1016–1035.E19. DOI: 10.1016/j. Wiese M, Bannister AJ (2020) Two genomes, one cell: Dr Sally Temple Institut Curie, Paris cell.2020.04.035. [Rawlins lab] Mitochondrial-nuclear coordination via epigenetic Neural Stem Cell Institute, New York pathways. Mol Metab 38: 100942. DOI: 10.1016/j. Ziv O, Price J, Shalamova L, Kamenova T, Goodfellow I, molmet.2020.01.006. [Kouzarides lab] Weber F, Miska E (2020) The short- and long-range RNA-RNA Interactome of SARS-CoV-2. 80: Wu B, Li L, Li B, Gao J, Chen Y, Wei M, Yang Z, Zhang Mol Cell 1067-1077.E5. DOI: 10.1016/j.molcel.2020.11.004. B, Li S, Li K, Wang C, Surani MA, Li X, Tang F, Bao S

Acknowledgements microscope at 10X magnification, labcoats & 76 by Peter Williamson; p visualised by staining cell nuclei (DAPI; 65 family day by Jelle van den Ameele, Photo and image credits cyan) and actin (Phalloidin; magenta). party costumes by Florence Leroy. Front cover image By Andy Li (Ma lab), who says “This Portrait photos Other images image shows the testis of Drosophila Group leaders by Chris Green, except: Research illustrations pp 4, 16 (l), 29, melanogaster expressing centrosomin- pp 3, 20 & 30 by James Smith; p 31, 33, 35, 37, 41, 45, 47, 51, 53 & 55: by GFP (green) and tubulin-RFP (red) and 28 by Eva Hörmanseder; p 44 by Claudia Flandoli; pp 6-7 coronavirus by stained to show cell nuclei (DAPI; blue), brandAnonymous; pp 22, 24, 46, 48, 52 & Onisha Patel; p. 16 (r): Damla Sarac; p.64 captured on the Leica SP8 confocal 54 unknown. Claudia Stocker. microscope at 630X magnification. The Research group and support staff photos Section-headers pp 8-9, 18-19 & 60-61: image has been processed to resemble by Chris Green except pp 24 & 54. details from oil sketches by Caroline a projection of the world map, to Walker. symbolise the international scientific Other photos community at the Gurdon Institute”. P 5 (l) and p 63 (MEP) James Smith; p Production 5 (mid and r) Natalie Glasberg; p 17 (l) Edited and produced by Claire O’Brien, Back cover image Naomi Clements-Brod, (r) Stephanie with thanks to Emma Gant, Daniel By Oriol Llorà Batlle (Brand lab). Norwood; p 56 Sylviane Moss; p 57 (r) Sargent, Hélène Doerflinger and Kathy Drosophila melanogaster salivary Al Downie; p 64 Miguel Salvador; pp 65 Oswald. glands, captured with an SP8 confocal Wellcome/ Cancer Research UK Gurdon Institute

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