Department of Medical Biochemistry and Microbiology IMBIM ANNUAL REPORT 2017 DEPARTMENT OF MEDICAL BIOCHEMISTRY AND MICROBIOLOGY ANNUAL REPORT 2017 Theses published at IMBIM in 2017 Edited by Veronica Hammar ISBN no 978-91-983979-3-2 PREFACE A university department is in its character a dynamic place. PhD students come and complete their education within 4-5 years. Postdoctoral fellows join for a relatively short time, maybe to change gears and learn a new field or just acquire more experience to become competitive for a tenure. Many researchers are recruited by groups where more hands and skills are needed. IMBIM is not an exception. But 2017 was extraordinary since the former Ludwig Institute for Cancer Research merged with IMBIM in August. This was of course a much welcome addition complementing and strengthening our research in cell and molecular cancer biology. As of the end of 2017 IMBIM had 165 employees and 105 registered with IMBIM as working place or employed elsewhere, but doing research at IMBIM. Here I would take the opportunity to welcome and congratulate Örjan Carlborg who 2017 was promoted to professor, Evi Heldin who was appointed guest professor and Kristofer Rubin who was also appointed guest professor and Director of BMC. During the month of May, the Quality and Renewal (KoF) evaluation panel visited IMBIM for two days of intensive discussions. Their assessment was also based on a self-evaluation most diligently assembled by IMBIM’s former Head of department, Göran Akusjärvi. It was as great pleasure to read the comment from the evaluation panel: “The self-evaluation report is an excellent summary of the current state of the department with ample and thoughtful self- reflection and self-criticism”. Many of the reflections in this text was in early Autumn addressed at a two-days department conference at Kolmården. Specifically, they were used as a starting point to discuss how IMBIM can improve, in particular regarding engagement, collaboration and communication. It was a reassuring to hear and feel the enthusiasm and engagement and it is promising that some ideas have already resulted in new activities and organisational changes. IMBIM is currently engaged in teaching at many different education programmes in areas closely linked to ongoing research, just as it should be. There is a slight bias where one research area is less involved. IMBIM’s Director of Studies has a mission to investigate the possibilities to develop new courses to ensure that there will be a good recruitment base of skilled and competent individuals for the future. Although it has previously been said that teaching is a burden, it is now gratifying to hear an increasing number of young scientists ask for the possibility to sign up. This means that the overall shift towards assessing research skills, pedagogic skills and cooperative skills more equally when recruiting for tenure track positions has become apparent and that career development requires own responsibility and insightful plans. Prizes and awards Leif Andersson and Kerstin Lindblad-Toh was awarded Uppsala University’s finest scientific prize for excellent research, Björkénska priset. Leif Andersson was appointed as International Member of the American Philosophical Society, Member of the National Academy of Inventors (USA) and Honorary Doctor at Texas A&M University. Mikael Sellin received one of the prestigious Ingvar Carlson Award 2017. On the local arena, Göran Akusjärvi was appointed Karl Johan Öbrink-Lecturer 2017. Even if Anna Knöppel has left IMBIM since her dissertation, we are proud that she received the Hwasser prize from Upsala Doctor’s association (Uppsala Läkareförening) for the best PhD thesis from the Medical Faculty. 3 For excellent pedagogic accomplishments, Per Jemth was awarded the “Limbiska priset” by students at the biomedical program. And then Lena Kjellén and Eva Engström who are course leader and course administrator, respectively on the course on Homeostasis and Endocrine Regulation, was for the second time in a row awarded the Optimus Prize by the student at the medical program for best course and best course administration. Highlights Research at IMBIM is strong and prosperous. This was clearly seen by a better than average result of approved research grant applications, 2017. This book describes all ongoing research at the department so here is just some highlights of a few areas to illustrate the width of what is going on. The tumour suppressor TGFβ (transforming growth factor β ) signalling pathway malfunctions when tumour cells progress towards malignancy. Aristidis Moustakas group has shown that in liver cancer cells, the nuclear receptor LXRα and TGFβ signalling cooperate in mediating cell cycle arrest, preserving hepatocyte identity and differentiation. LXRα signalling suppresses mesenchymal differentiation and reactive oxygen species induced by TGFβ. Malignant features in liver cancer are mediated by the transcription factor Snail, a pro- survival and mesenchymal inducer, whose expression is transcriptionally repressed by LXRα activation. Based on this mechanism, LXRα agonists, currently used to treat obesity, would promote the good side and would suppress the sinister side of TGFβ signalling in liver cancer. Bellomo, C., Caja et al. (2017) Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma. Cell Death Differ. doi: 10.1038/s41418-017-0021-3. The Darwin’s finches in the Galapagos archipelago are iconic models for the evolution of biodiversity. Leif Andersson and coworkers have shown that an immigrant male cactus finch was able to mate with a resident ground finch female and that the hybrid progenies bred with each other and established a new lineage of Darwin’s finches. It is very likely that new lineages have originated many times during the evolution of Darwin’s finches. The majority of these have gone extinct but some may have led to the evolution of contemporary species. Thus, the study illustrates how speciation can occur. Lamichhaney S, et al. (2018). Rapid hybrid speciation in Darwin’s finches. Science 359:224-228. After a per-oral vaccination with dead bacteria, large amounts of specific immunoglobulin A (IgA) is produced by B-cells of the gut mucosa. A study from Mikael Sellin and co-workers illustrate how the subsequent binding of such specific IgA to incoming live enteropathogens restricts separation of individual bacteria during the gut colonization phase. Gluing the bacterial pathogen together by the IgA coat blocks flagellar motility and hence mucosal attachment and tissue invasion. Moreover, since each individual bacterium within chains is only surrounded by its clonal kin, exchange of genetic material between bacteria is also efficiently prevented. In summary, this study explains a major mechanism-of-action of per- oral vaccine regimens. Moor K, Diard M, Sellin M, et al. (2017). High-avidity IgA protects the intestine by enchaining growing bacteria. Nature, 544(7651):498-502. IMBIM also encourage the offering of advanced method support to enhance cooperation and this year it is a pleasure to present two new possibilities. A specialized microscopy platform has been built by the group of Mikael Sellin. The main purpose of the microscope is to visualize the interactions between pathogenic bacteria and the gut epithelium in high spatial and temporal resolution. The platform is classified for work 4 with Biosafety level 2 and will be able to accommodate other researchers that wish to perform microscopy experiments on live pathogens, and other microorganisms. NMR spectroscopy is a versatile and powerful tool to study the structure, dynamics and interactions of biological macromolecules. Its application includes in situ study of functional properties of proteins and nucleic acids in live cells, including for example their physiological (post translational modification) and pathophysiological (amylogenesis) states. With two NMR spectrometers (600 and 500 MHz with cryogenic probes), IMBIM, together with the department of organic chemistry can perform different types of modern-day NMR experiments. March 2018 Catharina Svensson Head of the Department 5 LIST OF CONTENTS ADDRESS LIST 8 ORGANIZATION 13 SCIENTIFIC REPORTS OF RESEARCH GROUPS 16 Comparative Genetics and Genomics 17 Andersson Leif: Functional genomics in domestic animals and natural populations 19 Axelsson Erik: Genetic and functional characterisation of dog domestication 27 Carlborg Örjan: Computational genomics 28 Grabherr Manfred: Evolutionary bioinformatics and computational biology 32 Jern Patric: Retrovirus-host evolution 35 Lindblad-Toh Kerstin: Comparative genomics and genetics 37 Meadows Jennifer: Genetic dissection of autoinflammatory disease 46 Rosengren Pielberg Gerli: Comparative and Functional Genetics of Autoimmune Diseases 50 Rubin Carl-Johan: Identification and characterization of genes and mechanisms controlling phenotypic traits in horse and salmon 53 Webster Matthew T: Genome evolution 57 Medical Biochemistry 60 Glycobiology 60 Kjellén Lena: Cellular design of heparan sulfate 61 Li Jin-ping: Heparan sulfate and heparanase: Functions in homeostasis and diseases 65 Spillmann Dorothe: Glycosaminoglycans and heparanese 70 Medical Protein Chemistry 72 Chi Celestine: Conformational dynamics and in situ monitoring of posttranslational modification in biomolecules 73 Jemth Per: Structure – function relationships of proteins 74 Tomkinson Birgitta: Structure, function and physiological role of tripeptidyl-peptidase II 77 Tumor biology