Department of Medical Biochemistry and Microbiology IMBIM ANNUAL REPORT 2015 DEPARTMENT OF MEDICAL BIOCHEMISTRY AND MICROBIOLOGY ANNUAL REPORT 2015 Pictures taken by Helena Öhrvik The role of copper in mast cell granule homeostasis Ctr2 is a protein involved in cellular transport of copper. Upper panels: staining for tryptase, a mast cell granule protease, in tryptase (Mcpt6)-deficient (negative control), Ctr2-/- and wild type (WT) mast cells. Note that the absence of Ctr2 causes upregulated expression of tryptase. Lower panels: staining of Ctr2-/- and WT mast cells with toluidine blue, a proteoglycan- binding dye. Note increased toluidine blue staining of Ctr2-/- mast cells, indicating increased proteoglycan content of granules. Öhrvik, H., Logeman, B., Noguchi, G., Eriksson, I., Kjellén, L., Thiele, D.J., Pejler, G. (2015) Ctr2 regulates mast cell maturation by affecting the storage and expression of tryptase and proteoglycans. J. Immunol. 195, 3654-364. Edited by Veronica Hammar ISBN no 978-91-979531-8-4 PREFACE Another year has passed with both small and large successes for the laboratory. The Department has a stable staff consisting of some 150 people. Including project workers, post doc etc we are around 250 persons that spend our daily work hours at the Department. Fortunately the granting situation for the IMBIM researchers improved considerably during 2015. Many of the small and medium sized research groups received grants that will help them continue to excel during the coming years. In addition Dan Andersson, Leif Andersson, Per Jemth, and a couple of scientists at ICM, received a hefty 47 milj kr grant from “Knut och Alice Wallenbergs Stiftelse” to support their research on the evolution of new genes and proteins. We also congratulate Dan Andersson who was elected a member of “The Royal Swedish Academy of Sciences”, class for medical sciences. Further, we note that Leif Andersson received the 2015 Nilsson-Ehle medal from the Royal Swedish Academy of Forestry and Agriculture with the motivation “for outstanding research in molecular genetics with applications in animal genetics”. Also we congratulate Kerstin Lindblad-Toh who was elected a member of the Swedish Governments Science Advisory Board. It was also with great pleasure that we saw that the BSL3 laboratory for work with pathogenic organisms finally was delivered to BMC. Thanks to economic support from the faculty of medicine and pharmacy we could custom design a BSL3 laboratory in the form of a container that was assembled in France and delivered to us in early September. With some anxiety the container was finally lifted on top of the roof next to corridor A9:3 on September 11. After a period of testing everything appear to be functioning and we hope that the container should be in full operation during spring 2016. The media attention, in terms of press releases and newspaper articles that the Zoonotic laboratory has received during 2015 has been colossal. Much attention has been given to the building of the new BSL3 laboratory and the research activities of the zoonoses group. Their reports on highly pathogenic microorganisms carried by city rats, and campylobacter in ducks in Svandammen, are some of the well-cited examples. This type of media attention is most valuable to increase the public understanding of research and to improve the attitude towards science in general. While writing this section we were all saddened by the message that our long time coworker Barbro Lowisin has passed away after a long time struggle with cancer. Barbro was a remarkable woman that we all miss and never will forget. Scientific Highlights: Ongoing research projects at IMBIM are summarized later in this annual report. Below I have picked out a few examples of studies that illustrate the high quality and wide range of research carried out at our Department. Jenny Hallgren Martinssons group has, as the first group in the world, identified mast cell progenitors in human blood. Individuals with a reduced lung function had a higher frequency of blood mast cell progenitors than individuals with a normal lung function. These newly identified blood mast cell progenitor population provides a new therapeutic target for diseases were increases in tissue mast cells aggravate the disease (Dahlin et al., Blood). 3 Darwin’s finches and the evolution of their beaks is an iconic model for evolutionary biology. In a collaborative effort with the Princeton University Leif Anderssons group sequenced the entire genome of 120 birds representing all species of Darwin’s finches. The study demonstrated that genetic variation at the ALX1 locus, encoding a transcription factor with a pivotal role during craniofacial development, has a major effect on variation in beak shape. Thus, this locus has contributed to diversification of beak morphology among Darwin’s finches which has lead to an expansion of food utilization (Lamichhaney et al., Nature 518, 371-275). Anna-Karin Olssons group has found new clues to how cancer causes organ failure. They show that Neutrophil Extracellular Traps (NETs) acts to impair vascular function and to promote systemic inflammation. Removal of these tumor-induced NETs restored the vascular function in distant organs to levels seen in healthy mice and also suppressed the inflammation, demonstrating that the condition is reversible (Cedervall et al., Cancer Res. 13, 2653-2662). Malignancy in cancer depends on the ability of tumors to disseminate cells from primary sites of growth to other organs. In Aris Moustakas research group they study the molecular nature of cancer cell invasiveness with a hope to contribute to the development of new treatment modalities of cancer. The research focuses on the TGFβ (transforming growth factor β) and bone morphogenetic protein (BMP) families of signaling proteins. During 2015 Aris and his coworkers published a new study on regulation of BMP signaling by the tumor suppressor kinase LKB1, a mechanism that has relevance to developmental and cancer biology (Raja et al., Oncotarget). Teaching: Teaching of undergraduate and graduate students is a primary undertaking for IMBIM. During 2015 a total of nine students received their doctoral degree and two student a licentiate degree. The teachers at IMBIM does an excellent job something that is best illustrated by the fact that Linus Sandegren in 2015 received the “Limbiska priset” for the third time. The prize was awarded to Linus for his dedicated teaching in bacteriology. IMBIM congratulates Linus for this unheard-of achievement and expect to be able to use copy paste in the preface to the IMBIM book in 2017. The beginning of something new: During the coming year(s) the administrative and technical staff at IMBIM will have to set up mechanisms to handle an expanding Department. Thus, the Ludwig Institute for Cancer Research will merge with IMBIM in August 2017. This will create a major change in the research environment at IMBIM. The administrative and technical staff at IMBIM is of superb quality and does a fantastic job to support the research teams working at IMBIM. Without these effective support functions, the output in terms of research and teaching would rapidly deteriorate and the life for me as the head of the Department would become excruciating. 4 Finally, I would like to thank all of those who left IMBIM during the past year for your participation in building up this fantastic scientific environment. I wish you all the best for the future and hope that you only have fun memories from your time at IMBIM. At the same time I welcome all new students/scientists etc. to this exciting environment and hope that you will actively take part in the future development of this Department. Uppsala March 2016 Göran Akusjärvi Head of the Department 5 LIST OF CONTENTS ADDRESS LIST 8 ORGANIZATION 12 SCIENTIFIC REPORTS OF RESEARCH GROUPS 15 Comparative Genetics and Genomics 16 Andersson Leif: Functional genomics in domestic animals and natural Populations 18 Axelsson Erik: Genetic and functional characterisation of dog domestication 26 Bjerling Pernilla: Epigenetics and new antifungal drugs 27 Grabherr Manfred: Evolutionary bioinformatics and computational biology 29 Jern Patric: Retrovirus-host evolution 33 Lindblad-Toh Kerstin: Comparative genomics and genetics 35 Meadows Jennifer: Genetic dissection of autoinflammatory disease 48 Rosengren Pielberg Gerli: Comparative genetics of immunological diseases towards functional genomics 52 Rubin Carl-Johan: Identification and characterization of genes and mechanisms controlling phenotypic traits in horse and salmon 55 Webster Matthew T: Genome evolution 59 Medical Biochemistry 62 Glycobiology 62 Annerén Cecilia: Methods for maintanence and genetic manipulation of pluripotent stem cells 63 Kjellén Lena: Cellular design of heparan sulfate 66 Li Jin-ping: Heparan sulfate and heparanase: Functions in homeostasis and diseases 69 Ringvall Maria: The involvement of proteoglycans and glycosaminoglycans in cancer and angiogenesis 75 Spillmann Dorothe: What are glycosaminoglycans good for? 78 Medical Protein Chemistry 81 Jemth Per: Structure-function relationships of proteins 82 Tomkinson Birgitta: Structure, function and physiological role of tripeptidyl-peptidase II 85 Tumor biology 87 Johansson Staffan: Adhesion-dependent cell signaling 88 Moustakas Aristidis: Signal transduction and epithelial plasticity 91 Olsson Anna-Karin: Tumor vascular biology 96 Rubin Kristofer: Loose connective tissues – Potential targets for therapies in cancer and infectious diseases