Newsletter No. 11

July 2019 — National Center of Competence in Research, RNA & Disease

Message from the director’s desk

Phase 2 Contract Signed: Outcome & Outlook

Oliver Mühlemann, Director NCCR RNA & Disease

It is now almost 2 years ago when I could internationally renowned expert in genome other requesting a succinct plan on how to announce in “The Messenger” the decision editing. His profile and research interests convert a research finding into a product or a of the Swiss National Science Foundation match perfectly with our NCCR’s mission and concrete medical application. The application (SNSF) to grant a second 4-year phase for we are looking forward for fruitful collabora- deadline for both calls has meanwhile past our NCCR. Meanwhile, namely on May 1st tions with his team in the future. and the evaluation of the proposals has been 2018, this second funding phase has started While our various research projects are initiated. I am very curious to find out who in and the transition was so smooth that most making steady progress and the past year has our network will be able to develop the most of our members probably barely noticed it. seen many first publications originating from promising translational research projects. The management and the steering commit- collaborative research initiated among differ- Last but not least, a group of people led tee, however, were a bit nervous to start this ent NCCR member groups, a description of by our communication delegate David Gat- second funding phase without knowing what these projects here would go beyond the field and the scientific officers has worked the exact budget for the coming four years scope of this brief summary about the state intensively, but thus far mostly behind the will be. The feeling was like being in the of the network. Nevertheless, I want to reit- scene, to substantially boost and profession- middle of building a house – having to de- erate that I judge these collaborations to be alize our communication activities. The har- cide on many details regarding bath, kitchen the most important achievement and biggest vest of all these preparative efforts has yet to and roof – without yet knowing how much added-value of the NCCR RNA & Disease. come, but we can already look forward to the mortgage the bank is going to give you. The In terms of our networking activities, the soon launch of a new webpage addressed to decision on the funding level was dependent undisputed recent highlight was the joint the lay public with the main goal of getting on the SNSF’s comparative evaluation of all 8 retreat between our NCCR and the Vienna kids and young adults interested in life sci- NCCRs of the 4th series, which was finished RNA community near Salzburg in February ence. Ideas for entertaining and educational only in December 2018. (see page 5 in this Newsletter), and the next content for this website are highly welcome Our nervousness turned into relief and highlight is just around the corner: in Au- and should be forwarded to David, Larissa happiness, when just before Christmas we gust, the third NCCR RNA & Disease Sum- and Dominik. were informed that the NCCR RNA & Disease mer School “RNA Regulation in Health and was one of the three top-ranked NCCRs that Disease” will take place in Saas-Fee and the That’s all for now, enjoy reading this issue would receive a 7.5% increase in the SNSF organisers (Constance Ciaudo, Ana Marques of “The Messenger”! contribution. Making things even better, the and Raffaella Santoro) have put together a University of Bern thereupon decided to also great program with an amazing list of teach- increase their contribution by 7.5%. Our ers. When looking at the program, I wish I network had grown so much during the first could be a PhD student again. phase that we were preparing for substantial A topic that we have discussed on several financial cuts on many of our activities (as occasions in the past was that we should try outlined in our full proposal for phase 2), but to improve our efforts in developing our re- thanks to the unexpected additional money, search findings towards medical applications the extent of these cuts will now be more or into products that have the potential for moderate and essentially all planned projects commercialization. In order to incentivize can be implemented. all our members and associate members to Another positive consequence of the im- propose and develop such projects, we made proved funding situation is that we could two calls for postdoctoral fellowships (con- integrate into our NCCR as a full member sult the KTT section of the NCCR’s website), Jacob Corn, the new professor of genome one of them requiring a collaboration with Oliver Mühlemann signs the contract for biology at the ETH (since Oct 2018) and an clinicians at the Inselspital Bern, and the Phase 2 of the NCCR RNA & Disease. THE NCCR RNA & DISEASE MESSENGER, No. 11, July 2019 2

Interview with Matthias Hentze

“The field as such was not looking for such types of RNA-binding proteins.”

Interview: Dominik Theler

In this interview Matthias Hentze of decades ago. In China, I see a lot of appe- research besides the endurance that both of gives his perspective on pursuing tite to tackle things and to progress. Unless them require? an academic career and tells us about we somehow find a way to address that, we Patience. I would certainly not be able to the discovery of “non-canonical” RNA will fall behind. finish a marathon without it. You come to binding proteins and the “Riboregula- I do not know how it is here, but at in- points where you wish it is over soon, and if tion” concept. stitutions like EMBL, that should be exem- you still have 15 kilometers to go, you have plary, that provide an amazing infrastructure this urge to accelerate and get it done and and people with a key to work anytime 24/7 over with quickly. If you do this with 15 kilo- Where do you see the European research when they choose to, you are a bit surprised meters still ahead of you, you are not going landscape standing, also in comparison to by how few people you meet if you enter to make it to the finish line. There is a lot of China and the USA? labs on a Friday afternoon after five. this in science as well: you need the right There are many challenges. Europe is current- patience and strategy to make it along a long ly struggling more than maybe it was a few distance. years ago. I hope it finds out of that phase. I think the comradery and then the col- Regarding research, there are potential syn- legiality in sports is also very fitting to sci- ergies that we should make use of but are “I know, times have ence. I have been in marathon races where not. In a lot of places in Europe, there is fan- changed and this somebody was pushed in a wheelchair and tastic science going on, so on a small scale runners were taking turns to push the wheel- it is working well, but we are not obtaining a was a very lucky strike.” chair forward. I think this is wonderful at the commensurate more structured and strategic hobby runners’ level and also when it hap- benefit at the national or even continental pens in science: being ambitious for yourself level. but not against but together with others is a US research, I think, is currently going Being a researcher at EMBL provides you the fantastic parallel not just between marathon through a crisis. I hope it will recover soon, environment and resources to put it in soccer running and science, but sports and science. and I do not have any pleasure from a com- terms to play at the Champions League level petitive viewpoint that now, by comparison, research-wise, but doing so still requires per- How did you become a basic scientist after we are doing better because they have prob- sonal commitment. studying medicine? lems. I think the opposite is the case: The That is right: it requires personal commitment I started medical school because I wanted to better the science in the US, the more excit- and also dedication. You do not play Cham- treat patients, I finished medical school and I ing it is for European scientists to be part of pions League in soccer or Grand Slam finals still wanted to treat patients. I then wanted that global community. in tennis if you are not passionate about it to combine it with science becoming a physi- Both for US and for European research at every given moment, even on a Saturday cian-scientist in the area of gastroenterology the way that science is tackled these days in or on a Sunday. That sounds very old fash- and hepatology. I felt well prepared for the Asia, you specifically mentioned China, poses ioned, I know. I realize that not being in the a challenge. I think we have become in many lab does not mean that you are not working parts of the west a bit complacent about our on your research, particularly now that data work habits. They have become a little less analysis has become a much larger part of “I think we should not driven than at least I felt they were a couple experimental progress. There is a lot of data analysis that one can do in the comfort of only be judging out- home rather than in a lab where you have centrifuges running in the background. I re- comes but also paths.” “Interdisciplinary has alize that, but I still think that everyone who decides for a career in science should think become something about it similarly to entering a professional you can almost not do sports career: commit from day one, sweat it clinical part but ill prepared for the scientific out, win when possible and enjoy. part. Before starting with the clinical training, without.” I decided to enter for two years into scientific You are a marathon runner: What are the training for which I went to the NIH, joining parallels between running a marathon and the lab of Rick Klausner. THE NCCR RNA & DISEASE MESSENGER, No. 11, July 2019 3

Interview with Matthias Hentze

I worked on a project investigating a hu- the same environment. When you are a med- The situation may be somewhat differ- man genetic disease, hereditary hemochro- ical doctor and you lack some fundamental ent in areas where meaningful, high-quali- matosis, which failed miserably. However, in scientific knowledge, and I have to admit ty start-up companies are active and recruit the process, I cloned a human gene called that my chemistry knowledge still today well-trained scientists. However, too few ferritin. That was in the mid-eighties, and leaves much to be desired, you are constant- centers in Europe are currently successful in I saw a paper from the mid-seventies that ly in an environment with experts who can creating such environments. When I go to suggested that ferritin protein expression was help and advise, while you contribute your Boston or the Bay area, I see much more of regulated in a very unusual way. There were medical knowledge. that. I would say in those areas pursuing an big changes in the amount of ferritin protein academic career is potentially more attractive made when iron levels went up and down, because you have great science, but you also but no change at the mRNA level. In the have great alternative options. mid-eighties, it was totally exotic that you “If you make it is won- would have translational control. Is going from an academic career to an in- That was the claim of the paper, and since derful but if not that dustrial career perceived as a failure? I cloned the gene, I could actually test this For somebody in today, if they go directly and there were indeed big differenc- choice of a career path to a company setting, I would not at all say es in protein output without any change in that this would be looked at as a failure. I mRNA levels. Then I could stepwise identify might retaliate.” would definitely say that 15-20 years ago, it the responsible regulatory element which would have been looked at as your plan B, turned out to be the iron-responsive element but nowadays not. in ferritin mRNA. At the time, this was the I would like to comment on how to judge first element in a mature mRNA shown to be What were the biggest changes you wit- failure: I think we should not only be judg- regulating gene expression in a physiological- nessed over your career how science is done ing outcomes but also paths. Somebody can ly relevant way. and the scientific environment? take a very good path, learn a lot along that To cut a long story short, I then contribut- I think there is a scientific answer and a cul- path, but the outcome is unsuccessful: that ed to four ‘Science’ papers in two years: Two tural answer to that. Scientifically speaking, person has had a great learning experience, as a first author and two as a second author. of course, the ‘omics’. I used to be a reduc- which could be useful for many things and Rick strongly encouraged me to pursue a sci- tionist biochemist and now the omics and just because the outcome was not successful, entific career, but I insisted on wanting to systems biology have a big impact, and one is it should not be held against that person. practice medicine. He then suggested that I even asking mechanistic questions in a totally different way. Also, the emphasis on physio- What advice would you give to young re- logical experimental conditions has changed searchers? dramatically. Those would be the two com- Make up your mind about what you want ponents of my scientific answer. and what would be your dream - and then “I thought ‘wow’ if this In terms of culture, interdisciplinary has try to pursue it with all that you have. Do is a general principle become something you can almost not do not limit yourself by what you think would without, which means that a single person give you greater chances in the future based that would be quite and sometimes even a single lab can achieve on probabilities, because these things change much less. Therefore, there is less autonomy and your best guarantee to have a successful amazing.” of individual labs than there used to be, but career is to work in something that you are in turn, there are far more collaborations that truly passionate about. I am not recommend- are exciting and yield profound insights. ing to be a dreamer, but to realize what your dream is and to pursue it in a strategic way. go to EMBL to give a talk. I gave a talk and Is an academic career still as attractive as without even applying, I was offered a group when you started your group? Your group developed the RNA interactome leader position to my total surprise and I You would have to ask the younger people capture method and applying it identified took it. I know, times have changed and this this question. I think yes. It depends on what numerous novel RNA binding proteins: Were was a very lucky strike. And while this career you want from your professional life. I think you surprised how many there were? change was totally unplanned and opportu- there is not a small fraction of people who Absolutely. We actually did not develop the nity-driven, it turned out to be one of the would like to have a secure job ideally before RNA interactome capture method as a way best professional decisions that I ever made. the time they start their families, which is to- to discover or describe the RNA binding pro- tally understandable. I think that academia teome as a whole. I simply wanted to know Would you still study medicine before enter- the way we still practice it today, does not of- whether other metabolic enzymes could bind ing a basic research career in the life scienc- fer that. This situation deters talented young RNA. “My first protein”, iron regulatory pro- es? people because they prefer to take a track tein 1, which is identical to cytosolic aconi- I would say, it did not hurt me, and even if that is more predictable in terms of career tase, was an example of an RNA-binding pro- people have an interest in biomedical sci- outcome. One of the big disadvantages of an tein, which is at the same time an enzyme, ence, I would advise them to consider study- academic career, today in particular, is that and where metabolic changes introduce ing medicine rather than biology, genetics or if you make it is wonderful but if not that switching between the RNA binding and the biochemistry. The reason is that only when choice of a career path might retaliate. You metabolic function. you study medicine, you really have the may struggle, at least for some time, before I thought “wow” if this is a general prin- chance to learn what medicine is about. you find your bearings in an alternative ca- ciple that would be quite amazing. We need This knowledge is very hard to acquire for a reer. In that sense, academic jobs have be- to connect cellular metabolism with cellular non-medic because non-medics do not have come less attractive. gene expression programs, and that would THE NCCR RNA & DISEASE MESSENGER, No. 11, July 2019 4

Interview with Matthias Hentze

be a wonderful, potentially general way of In my opinion, about 30 years of RNA bi- how this could happen. There were papers ology were mostly driven by looking for reporting on a few other examples, like GAP- trans-acting factors that regulate . DH and enolase, being RNA-binding proteins. Researchers performed affinity purifications I just wanted to know if this could be more a using RNA regulatory elements and looking general principle. for RNA-binding factors; or screening genet- So we thought of the RNA interactome ically for factors that influence RNA fate. So capture method and Markus Landthaler’s RNA-binding proteins that bind to RNA and group - for different reasons - developed the regulate RNA were found: this outcome was same technique independently in parallel. inherent to the way they were looked for. Then we had the outcome and I was delight- Now we have what is commonly referred to ed to see how closely ours and Markus’ data as ‘unbiased’ approaches. And we not only agreed with each other and that there were ‘rediscovered’ these classical trans-acting seventy or so enzymes. Far more than we factors, but also found those that would bargained for, giving us more than enough not likely have been found before, because to work on. they do not have those roles, and are instead regulated by RNA. The field as such was not looking for such types of RNA-binding pro- Matthias Hentze “You need the right teins. Biography

patience and strategy Might there be even more RNA-binding pro- After completing his medical studies at teins that were missed by the interactome the University of Münster Matthias Hentze to make it along a capture method? joined the lab of Rick Klausner at the NIH long distance.” How many have we still missed? I do not Betsheda in 1985. In 1989, he became know. We currently estimate the number group leader at the EMBL Heidelberg. In for mammalian systems to be somewhere 1990, he obtained his habilitation from between 1500 and 2000, and interactome the University of Heidelberg and in 1998 However, there were all these other pro- capture has been devised to be low on false was promoted to senior scientist at the teins, and initially, when I saw them, they positives while accepting false negatives. EMBL Heidelberg. From 2005 – 2013 he made me worry. How can that be? These pro- False negatives can arise because UV cross- served as associate director of the EMBL teins had nothing to do with RNA, as far as linking is very inefficient, and there might be Heidelberg and in 2013 became its di- we knew. Do I expect them all to moonlight circumstances when a facultative RNA-bind- rector. Since 2002, he is the co-director and have a second function or is something ing protein is not active in RNA binding; for of the “Molecular Medicine Partnership wrong with the technique? Do we have many example, it might only bind RNA in mitosis Unit” of the EMBL and the University of false positives for some reason? I was really or under stress. Therefore, there are plenty Heidelberg. In 2011, he was awarded an struggling with that for a while. of reasons for why we might still be missing ERC Advanced Grant entitled “Exploring Until I had the thought that these find- some. the interface between cell metabolism ings connected well with the RNA world and gene regulation: from mRNA interac- hypothesis and the origins of life. The role You discovered these metabolic enzymes tomes to ‘’REM Networks’”. that RNA might have played very early in binding RNA: On how many of these were evolution was to regulate protein functions. follow up studies performed to reveal the Hentze Lab Website Therefore, these proteins might not bind RNA mechanistic details? to regulate RNA expression as trans-acting Not many at all at this point and the explo- factors, for example splicing or RNA stability, ration is just beginning. Cytosolic aconitase RNA scientists in Switzerland and the NCCR but some proteins could be bound by RNA was there before and inspired the work. We RNA & Disease brings them together. But it to be regulated by RNA, which we now call have published a paper on a mitochondrial not only brings together the principal inves- Riboregulation. dehydrogenase, HSD17B10, but this is quite tigators but also the students. After speak- limited work. I have heard that around the ing to them both in Bern and Zurich, I can A reversal of roles? globe, some groups are picking up some of say that they are really happy that the NCCR Exactly, suddenly we realized that RNA-pro- these enzymes and study their RNA binding connects them. tein interactions could potentially exert the in more detail. However, I must also say that I In Zurich, some students remarked that, in same type of regulatory functions that we am slightly disappointed. Our paper and that their view, there was limited connectivity of are accustomed to from protein-protein in- from Markus Landthaler were published in PhD students between different departments, teractions. From SELEX-derived aptamers 2012, and if you had asked back then how but that those who are in the NCCR-run we know that RNAs can evolve to bind to much will we know in 2019, I would have ex- RNA Biology PhD program feel privileged be- nearly any surface, including protein surfac- pected more. I hope that this is still coming. cause it provides a way that connects them es. So RNAs could have evolved to binding to We will definitely try to make our contribu- creating a community that exchanges and proteins that lack recognizable RNA binding tions and we are currently tackling several benefits from each other. I cannot evaluate domains. This concept of ‘Riboregulation’ is additional enzymes; however, this takes time. this statement, but I found it a very genuine what we are very excited about right now, statement. So from that angle, this program and which we intensively investigate further. What has been your impression of the NCCR is providing fantastic glue towards not only RNA & Disease during your visit? connecting PIs but connecting communities Why was the RNA binding capability of these This is not a political statement: I think it is and fulfilling a very important training pur- proteins not discovered before? great. There is a good number of outstanding pose for the involved students. THE NCCR RNA & DISEASE MESSENGER, No. 11, July 2019 5

Networking across borders

Austrian Swiss RNA Meeting

This year’s annual retreat of the NCCR RNA & Disease took place in form of a special edition as a joint meeting with the Vienna RNA Biology Network.

Over 200 scientists from more than 60 Swiss and Austrian laboratories met in the beauti- ful area of Fuschlsee near Salzburg, Austria, from January 30 – February 3, 2019. 5 days of intensive scientific interactions including excellent oral and poster presentations by the participants stimulated scientific exchange and aimed at initiating and fostering collabo- rations between established and junior scien- tists from the Vienna and Swiss RNA commu-

“Everyone I talked to said it was their favorite retreat they had ever been to, myself included.” Participants attending the opening session

“It was really amazingly well organized at all levels. The place was gorgeous, the science absolutely great, the possibilities to interact with colleagues fre- quent and everything ran really smoothly.”

Discussions during coffee break THE NCCR RNA & DISEASE MESSENGER, No. 11, July 2019 6

Networking across borders

nities. The meeting covered a broad spectrum event! A special thank goes to the Scientific of topics related to bacterial RNA networks, Advisory Board Members Sarah Woodson, non-coding RNAs, RNAs in gene regulation, Witold Filipowicz, Jørgen Kjems and Robert “I think mixing with RNA processing, RNA modification and trans- J. Schneider for their continuous support and another network was a joining us at Fuschlsee. This meeting was kindly supported by Lex- great idea that could be ogen, VectorBuilder, The RNA Society, New “A joint meeting with England Biolabs and Microsynth. repeated in the future. Enriched with impressions and ideas col- another RNA network lected during the Austrian Swiss RNA Meet- It was a very successful ing, we are already looking forward to to the was really interesting next annual retreat to be held in Kandersteg, experience.” Switzerland, from January 27. – 29. 2020. and stimulating.”

lational regulation. The researchers benefited from the opportunity to present their work to an audience of peers and established princi- pal investigators in their field. The format of the meeting provided plenty of opportunities for networking and discussions. We would like to thank the Austrian and Swiss organizers and all participants for con- tributing to such a successful and inspiring

“Really nice atmosphere, notably during poster sessions, which allowed open and interesting discussions.” Lake Fuschl

Poster viewing THE NCCR RNA & DISEASE MESSENGER, No. 11, July 2019 7

Swiss RNA Workshop 2019 Bringing Together the Swiss RNA Research Community

On January 25, 2019, the 20th edition This year’s keynotes were delivered by Eric For their financial support, we would like of the Swiss RNA Workshop took place Miska (Gurdon Institute, University of Cam- to thank the RNA Society and the company at the University of Bern, which was bridge, United Kingdom) on “An ancient sponsors Axonlab, Fisher Scientific, Horizon, attended by over two hundred partici- machinery drives piRNA transcription in C. Macherey-Nagel, Merck, Microsynth, Qiagen pants. elegans” and Alena Shkumatava (Curie Insti- and Takara. tute, Paris, France) on “Dissecting the in vivo The 21st edition of the Swiss RNA Work- The first edition of the workshop took place functions and mechanisms of action of ln- shop will take place on Friday, January 24, in 1995, organized by Angela Krämer and cRNAs”. Fourteen short talks were presented 2019, in Bern. Daniel Schümperli. The workshop continues that were selected from submitted abstracts bringing together RNA researchers from Swit- and fifty-nine posters presented covering a zerland and neighboring countries for a one- wide range of RNA research topics. day meeting.

Keynote speaker Eric Miska (right) discussing with Rory Johnson (left)

Conversation between keynote speaker Alena Shkumatava, Oliver Mühlemann, Lunch and poster session Jeff Chao and Ramesh Pillai (right to left).

Talk session THE NCCR RNA & DISEASE MESSENGER, No. 11, July 2019 8

Research highlights Research highlights from NCCR laboratories Roland Fischer

Still conFUSed?

Fused in Sarcoma (FUS) is an RNA binding betasheet surface, as expected for an RRM. It is a complex story, indeed. The results protein associated with several neurode- However, the path taken by these nucleotides not only open up interesting new paths for generative diseases. RNA binding has been is unusual, with the three nucleotides form- further research, but also help understand suggested to be crucial for FUS function and ing a tight turn rather than a straight line. why deciphering the RNA binding mode of recent research has shown that FUS has the Most contacts are of non-sequence-specific FUS has been so challenging. “This was a intrinsic ability to bind many RNAs without nature, with hydrophobic interactions and very difficult structure to solve due to the substantial differences in binding affinity. contacts to the phosphate backbone. very dynamics nature of the interaction of The actual mode of nucleic acid binding RNA binding by FUS is important in facil- the RRM with the RNA. But I am glad this has been elusive, so what exactly determines itating efficient liquid-liquid phase separa- could be achieved, thanks to the heroic effort the FUS interactome in vivo has become one tion into membrane-less compartments like of Dr. Fionna Loughlin (mother of two with of the big unanswered questions in the RNA liquid droplets, the aging of which could 120% SNF support and now back to Austra- field. Finally, Loughlin et al. from the Allain lead to aggregation of FUS in ALS and FTLD lia) and a great collaborative effort from four group (Institute of Molecular Biology and patients. The modular nature of FUS RNA NCCR groups” said Prof. Fred Allain. Biophysics, D-BIOL, ETH Zürich) managed to binding and the weak RNA binding affinity solve the solution structure of FUS bound to of the folded domains shown here are per- Louglin F.E. et. al. (2019) Molecular Cell RNA, revealing a sequence-specific recogni- fectly consistent with the weak multivalent 73(3), 490-504.e6 tion for a GGU motif and an unusual shape interactions known to facilitate phase tran- recognition of a stem loop by two separate sition. This multivalent RNA binding, togeth- domains. er with the disordered regions of FUS, are This is not only interesting on a theoretical well suited to play a role in the formation level: FUS plays an important role in regulat- of the different phases, and the RRM and ing genetic messengers and the interaction ZnF have recently been shown to contrib- of different proteins. FUS mutations lead to ute to RNA-mediated phase separation of FUS accumulations in the cytoplasm. The two FUS. Furthermore, the role of RGG regions neurodegenerative diseases amyotrophic lat- in destabilizing structured regions of RNA in eral sclerosis (ALS) and fronto-temporal lobar addition to direct binding may further facil- degeneration (FTLD) show neuropathological itate this process. protein aggregates containing FUS, and it is hypothesized that mis-regulation of RNA processing could play a major role in these diseases. Transcriptomics studies have already indi- cated that FUS binds a large variety of RNA motifs, suggesting that FUS RNA binding can only be explained with a complex pattern. The findings of Loughlin et al. finally shed some light on the binding mode of FUS. With the help of colleagues from the Department of Chemistry and Biochemistry of the Univer- sity of Bern (Mühlemann and Ruepp’s labs) FUS RRM - RNA FUS ZnF - RNA and the Institute of Molecular Life Sciences of the University of Zürich (Polymenidou’s lab), the structure solved by the Allain group that revealed a bipartite binding mode of RNA via its RRM and zinc-finger (Znf) could be func- tionally validated in cell-based assays. The ZnF provides sequence specificity to FUS, whereas the FUS RRM binds stem-loop FUS RRM - RNA FUS ZnF - RNA RNAs in an unusual manner and with highly degenerate specificity. The structure of the FUS RRM bound to the stem-loop RNA re- veals three individual binding pockets on the Picture kindly provided by Antoine Cléry. THE NCCR RNA & DISEASE MESSENGER, No. 11, July 2019 9

Research highlights

Turbocharger for the cell machinery

That’s how we’ve learned the molecular- sickness, are known for their unique molec- stress, ncRNA molecules attach to ribosomes, biological narrative in school, in its ular biological apparatus. In the absence of as if pushing the emergency stop button of classic simple form: Gene-RNA-protein. DNA extensive transcription control mechanisms the protein machinery. When nutrients be- is transcribed into RNA and the RNA serves the parasite crucially depends on come scarce or environmental conditions as a kind of punch card in the ribosomes – regulation to orchestrate gene expression. become especially challenging, the entire the proteins are assembled by the machinery However, molecular insight into regulating assembly line is shut down, saving time for according to the DNA template. In recent de- protein biosynthesis is sparse. The Polacek the cell. ncRNA molecules are predestined cades, however, biologists have realised that and the Schneider groups analyzed the small for such a regulatory mechanism – they are this scheme is far too simple, in particular non-coding RNA (ncRNA) interactome of ri- produced within fractions of minutes and can with regard to the role of RNA. More and bosomes in T. brucei during different growth thus trigger a fast reaction of the cell. But more RNA has been found bearing no code, conditions and life stages. Ribosome-associ- an acceleration of production? This irritated i.e. no protein instructions. Today, it is as- ated ncRNAs have recently been recognized the researchers in two respects: Firstly, it is sumed that in most living organisms the ma- as unprecedented regulators of ribosome not immediately clear what the purpose of jority of RNA produced is actually “non-cod- functions. The researchers have identified such a regulation might be, and secondly, ing”. In humans, noncoding RNA makes up one especially intriguing ncRNA, the tRNAThr it is much more difficult to come up with an amazing 98 percent of RNA. Why is so 3´half. It is produced during nutrient depri- an intuitive mechanism for such a mode of much RNA transcribed not serving the “clas- vation and becomes one of the most abun- operation. “We knew of inhibitors, which sical” purpose? As simple as the question is, dant tRNA-derived RNA fragments (tdRs). typically block important binding sites,” said it still offers plenty of surprising answers. tRNAThr halves associate with ribosomes and Norbert Polacek, the head of the research As reported in Nature Communications, polysomes and, once starvation conditions group. He believes that the ncRNA fragment Researchers from the Polacek and the Schnei- ceased, stimulate translation by facilitating has the effect of bringing the ribosomes up der groups of the University of Bern have dis- mRNA loading during stress recovery. to full production capacity without delay as covered a new molecular regulatory mecha- These findings astonished the researchers soon as, for example, sufficient nutrients are nism in the unicellular parasites Trypanosoma because until now only the opposite function available again - Polacek calls it a “kick start” brucei never described before. Trypanosomes, of non-coding RNA had been known, acting for the cell. parasitic protozoa responsible for sleeping as inhibitors for the cell apparatus. During Blocking or depleting the endogenous tR- NAThr halves mitigates this stimulatory effect both in vivo and in vitro. T. brucei and its close relatives lack the well-described mam- malian enzymes for tRNA half processing, thus hinting at a unique tdR biogenesis in these parasites. The exact mechanism re- mains unclear, however, and Polacek believes this opens up an interesting field for further research. Furthermore, the findings widen the understanding of the regulatory potential of tdRs in general, as compared to other small ncRNA regulators. The researchers do not exclude the possibility that the T. brucei tR- NAThr 3’ half has additional biological roles in the parasite beyond translation control. They find it “astounding” that the “precursor” molecule of tdRs, genuine tRNA that is, has basically one major cellular role as substrate for the protein synthesis machinery, while processing products thereof are functionally so heterogeneous. Thus post-transcriptional cleavage events can generate novel regula- tory molecules thereby further increasing the complexity of cellular RNomes in general and expanding tRNA biology in particular.

Fricker R. et al. (2019) Nature Communica- tions 10(1),118 (open access)

Picture kindly provided by Norbert Polacek. THE NCCR RNA & DISEASE MESSENGER, No. 11, July 2019 10

Announcements

People Support Grants As of the beginning of the year Jacob Corn became full principal Please visit our webpage for more information on the Lab exchange investigator of the NCCR RNA & Disease. program, the Doctoral mobility grant and measures in equal oppor- tunities. We would like to welcome Christa Flück, Françoise Stutz and Karsten Weis as new associate members of the NCCR RNA & Disease. Christa Flück is the head of the endocrinology, diabetes and me- tabolism unit of the University Hospital of Bern Pediatrics Division NCCR Bio-Inspired Women in and principal investigator at the Department for BioMedical Research Science Postdoctoral Fellowship (DBMR). Her lab's primary research interest is human steroid biology. Françoise Stutz is full professor at the University of Geneva and her The NCCR Bio-Inspired Materials made a new call of their Women lab researches several aspects of RNA metabolism including mRNA in Science Postdoctoral Fellowships. The fellowships funds research biogenesis and export as well the roles of nuclear architecture and conducted in laboratories of the NCCR Bio-Inspired Materials. Please non-coding antisense RNAs in gene expression regulation. Karsten follow this link for more information. Weis holds a full professor-ship at the ETH Zurich and research in his lab deals with intracellular macromolecular transport especially across the nuclear pore complex, mRNA degradation and the function of membrane-less organelles like P-bodies and stress granules. Upcoming events organized by or involving the NCCR RNA & Disease We congratulate Michael Hall for receiving the 2019 Howard Taylor Ricketts Award and the 2019 Nakasone award. Congratulations to > NCCR Seminar Series Autumn Semester 2019: the NCCR’s Scientific Advisory Board Member Adrian Krainer (Cold Christine Mayr (Memorial Sloan Kettering Cancer Center, Spring Harbor Laboratory) for being awarded the 2019 RNA Society New York, USA), September 23, University of Bern Lifetime Achievement Award. & September 24, 2019, ETH Zurich Bryan Cullen (Duke University, Durham USA) October 7, University of Bern & October 8, 2019, ETH Zurich NCCR RNA & Disease Chimia Issue David Bartel (Massachusetts Institute of Technology, , USA) October 14, University of Bern & October 15, 2019, The May issue of the Chimia journal is a topcal issue on the NCCR ETH Zurich RNA & Disease. Member and associate member groups contributed Paul Anderson (Harvard Medical School, Cambridge, USA) eight review articles and the editorial was written by the co-directors. October 21, University of Bern & October 22, 2019, ETH Zurich Phil Bevilacqua (Pennsylvania State University, Pennsylvania, Link to the NCCR RNA & Disease Chimia issue. USA) November 18, University of Bern & November 19, 2019, ETH Zurich

NCCR Technology Platforms The NCCR RNA & Disease has two new bioinformatics support per- Jobs sons in Basel and Zurich. Dr. Michaela Schwaiger is based at the PhD program in RNA Biology Friedrich Miescher Institute in Basel, while Dr. Markus Schröder is at Find out more on the PhD program website. the Molecular Health Sciences Platform at ETH Zurich. Dr. Julius Rabl at ETH Zurich is the new contact person for Cryo-EM support. Check the jobs’s section of the NCCR RNA & Disease webpage for other openings. Visit the technology platform website of the NCCR RNA & Disease for more information and the contact details.

IMPRINT Office Bern University of Bern The National Centres of Competence Departement of Chemistry and Biochemistry in Research (NCCR) are a research instrument Freiestrasse 3, CH-3012 Bern of the Swiss National Science Foundation Office Zürich NCCR RNA & Disease ETH Zürich Phone: +41 31 631 38 12 Institute of Molecular Biology & Biophysics office@nccr--and-disease.ch ETH-Hönggerberg, HPP L15 www.nccr-rna-and-disease.ch Otto-Stern-Weg 5, CH-8093 Zürich