A study done on fruit flies and published in Nature Communications reveals that the protein dDsk2, in addition to degrading proteins, also plays a key role in regulating gene expression.

This protein is also present in humans and is known to be mutated in several neurodegenerative diseases, including Alzheimer’s. But the mechanism by which these mutations contribute to the development of disease remains unclear.

IRB Barcelona is to start a study to examine the relationship between dDsk2 mutations and neurodegenerative diseases.

Until today, the proteins known as ubiquitin receptors have been associated mainly with protein degradation, a basic cell cleaning process. A new function now described for the protein dDsk2 by the team headed by Ferran Azorín, group leader at the Institute for Research in Biomedicine (IRB Barcelona) and CSIC research professor, links ubiquitin receptors for the first time with the regulation of gene expression. This discovery, published today in Nature Communications, opens up a double scenario, one focused on basic epigenomic research and the other biomedical, because of the link between dDsk2 and neurodegenerative diseases.

Double role of ubiquitin

In humans, there are about 100 proteins associated with ubiquitination, the process by which a protein labelled with ubiquitin is removed from the cell by specific cell machinery known as the proteosome. Ubiquitin receptors are involved in the detection of ubiquitination.

Ferran Azorín, head of the “Chromatin structure and function” group says, “although previous data pointed to the possibility of ubiquitin receptors also contribute to cell processes, data were scarce and a direct role in gene regulation had not been demonstrated.”

“Ubiquitination related to transcription proteins and to DNA repair had previously been described. But this is the first time that a protein, dDsk2, that recognises the ubiquitination of a histone, a protein that forms part of chromatin, has been identified.” Chromatin is a complex formed by DNA and histones —proteins tightly bound to DNA— packaging it into chromosomes and determining gene expression, a process known as epigenetics.

Recent years have brought about the discovery of the fundamental contribution of epigenetics to the development of disease. “We have now opened a new perspective for ubiquitin receptors and we should further this research”, explains Roman Kessler, a Swiss “la Caixa” PhD fellow at IRB Barcelona and first co-author of the paper. In the study, the researchers also reveal the molecular mechanism through which the protein dDsk2 binds to chromatin proteins, thus participating indirectly in the regulation of transcription.

The protein in neurodegenerative diseases

Subjects with Alzheimer’s disease and other neurodegenerative pathologies such as Huntington’s, have a mutation in the protein ubiquilin, the homologue of dDsk2 in humans. “The role of these mutations in the onset and development of disease is still unknown,” says Johan Tisserand, postdoctoral research and co-author of the study who is continuing with the project. “Now that we have discovered this new function, we aim to study whether it affects degradation or transcription, although probably both processes are altered. Our goal is to work towards unravelling these effects,” concludes Ferran Azorín. The new studies will be performed on Drosophila melanogaster and in cells in vitro.

Reference article:

Roman Kessler, Johan Tisserand, Joan Font-Burgada, Oscar Reina, Laura Coch, Camille Stephan-Otto Attolini, Ivan Garcia-Bassets and Fernando Azorín (2015) The ubiquitin receptor dDsk2 regulates H2Bub1 and RNApol II pausing at dHP1c-complex target genes  Nature Communications DOI: 10.1038/ncomms8049

This article was first published on the 28th of April 2015 in the news section of the IRB Barcelona website

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About a year ago – when spending some quality afterwork time on the Internet – me and my benchmate Dario stumbled upon LilBUB. If you’re an internet cat afficionado you’ve probably seen LilBUB around. She’s extremely cute and lovable, and she’s got something of a celebrity status. But, as developmental biologists, we were also intrigued by her in a different way. Which is why, two weeks ago, we launched a crowdfunding campaign to sequence the genome of LilBUB. This is the story of our campaign so far.

Remember: there’s only one BUB.

LilBUB is not only terribly cute, but she was also born with a strange combination of phenotypic traits. She’s polydactyl (one extra digit on every paw), she’s really small, has a short jaw, possibly some sort of skull bossing, and so-called Erlenmeyer-flask bones. All of the latter traits hail from a very strong bone overgrowth diagnosed as osteopetrosis type IV, but the vets were unsure in their diagnosis. Finally, the bone overgrowth led to her jaws mineralizing too quickly, preventing almost all of her teeth to emerge. Also, since her tongue developed to normal length, it’s hanging out most of the time.

From human to cat genetics

Dario and I are postdocs at the Max-Planck Insitute for Molecular Genetics in Berlin. The focus of our work is to uncover the developmental pathomechanism underlying disease-causing mutations, which have been identified by our human geneticist colleagues. We primarily study mutations affecting limb patterning and bone biology. So we couldn’t help but notice the parallels between the patient-cases that we usually deal with and the phenotype of LilBUB.

Surprisingly though, while we could assign individual traits of LilBUB to one human disorder or another, her combination of traits (with polydactyly AND osteopetrosis) is unique and unlike any case we know. We immediately started hypothesizing what kind of mutation could cause her special looks. Did she have a new form of osteopetrosis? Or was she suffering from two rare diseases? We were super-curious really wanted to find out. So we wrote an email to BUB’s owner, asking if he would allow us to sequence LilBUB’s genome. The reply came within five minutes – he was totally up for it!

The power of the crowd

Having decided to sequence LilBUB we quickly realised that this should not be a traditional project, done somewhere in an isolated laboratory and then communicated only in a scientific journal.

1. First, LilBUB is at home on the Internet. She has thousands of followers – it should only be fair that they might want to share LilBUB’s scientific journey with us.
2. Second, LilBUB has a set of traits that resemble rare developmental diseases. Because they only affect very few people, such diseases often don’t get enough attention in the media, even though they can be devastating. Discussing our search for LilBUB’s mutation would make it possible to create awareness for these diseases.
3. Finally, we were unlikely to get traditional funding: BUB’s an isolated case and an orphan, limiting the experimental approaches we could take.

Thus, we came up with the idea to crowdfund the project, to create some sort of hybrid of classical lab work, outreach and citizen science – and whatever else it would evolve to be. This way we could make thousands of people around the world co-owners of the project, and share our quest with them.

Preparing for battle

Months of preparation followed. First, we joined forces with Uschi, a former collaborator of ours, who had worked on polydactyly during her PhD. She was incredibly enthusiastic about the project, but equally importantly she also brought experience in science communication to the team. As a trio we then set up a project website and social media accounts, scripted a crowdfunding video, and devised a strategic plan for experiments and outreach. Most importantly, following months of brainstorming we came up a name: from a combination of LilBUB + genome, we created the LilBUBome!

And so, two weeks ago, we launched the crowdfunding campaign for the LilBUBome, as well as an accompanying blog, facebook and twitter account. The project launched simultaneaously with it’s sister project, the 99 cat lives initiative by Prof. Leslie Lyons from the University of Missouri. Leslie is an expert in cat genomics, and the 99Lives intends to sequence 99 cats from all over the world to figure out the genetic basis of feline biology and disease. It’s a great combination, when we get to sequence LilBUB we’ll have Leslie’s expertise and plenty of other data to use as a reference, and two projects hopefully reach more people than only one. There could have been no better time fort he LilBUBome than now.

First conclusions

After 2 weeks of fundraising this is what we know: It’s exciting. It’s fun. We love the interactions with our backers and followers. But in one respect it’s just like most other lab-related work: we don’t know whether it’ll work. If we fail to raise the money until May 24th, we get nothing! So, if you’re as curious as we are about the causes behind LilBUB’s magical looks, please spread the word, like, share and maybe even directly support us!

Daniel

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Currently NIH has put out a request for information (RFI) to solicit input from the scientific community regarding “Optimizing Funding Policies and Other Strategies to Improve the Impact and Sustainability of Biomedical Research”(NOT-OD-15-084). The deadline to submit a response is May 17^th 2015. More information can be found at Rock Talk blog post. Response need to be submitted at this website. 

NIH intends to maximize the impact of taxpayer investment in biomedical research by A] maximizing the productivity and creativity of the research workforce it funds,  B] ensure funding for a broad and diverse group of investigators studying a wide range of important questions. 

A response (unabridged version) submitted to this RFI is opened here. With the hope and intention of stimulating the scientific community to submit a response of their own as well as criticize, debate and use as resource, the points in this response.

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The Young Embryologist’s Network is an organization in the UK – you may have seen the recent call for abstracts for the UK annual meeting – that is expanding to Boston! The aim of the first few Boston meetings is to bring together anyone with an interest in embryology and development to hear undergraduates, graduate students and postdocs give 20 minute talks about their work. Food and drink will be provided (for the May and June meetings, by the Dept of Systems Biology at Harvard Med School) for discussions and mingling afterwards.

Please get in touch (gary.mcdowell@tufts.edu) if you’d like to give a talk (events will be in May, June and resume after the summer), and please come along to listen! Please see the poster for more information and contact details.

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This week a group in China published a paper in Protein & Cell claiming to have genetically edited a human embryo using CRISPR technology. This paper is generating a lot of debate for many reasons, from the type of embryo used in the experiment, to where it was (or wasn’t) published. More broadly though, it forces us to think about the ethics of such work, especially since there are reports that other groups are also attempting similar experiments. So this month we would like to know:

Has CRISPR technology developed too quickly, before there has been the time to consider its technical hurdles and the ethics of its applications in certain systems, most notably human embryos?

Further reading:

– Link to the paper by Huang and colleagues: CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes

– News article in Nature reporting on this paper

– Also check out this discussion in Nature last month, as well as a set of recommendations published in Science.

Share your thoughts with the community by leaving a comment below! You can comment anonymously if you prefer. We are also collating answers on social media via this Storify. And if you have any ideas for future questions please drop us an email!

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Here is April’s round-up of some of the interesting content that we spotted around the internet!

News & Research

– There is a growing number of postdocs and not enough positions in academia. What is the future of the postdoc? Meanwhile, the MRC removed the number of postdoc years from their eligibility criteria for fellowship applications.

– Rumour has it that DNA editing techniques are being used in human embryos. Here’s the discussion in Nature, and a set of recommendations published in Science.

– What do fossils oviraptor eggs tell us about dinosaur development? An interesting article in Embryo Project.

– ‘The Thrill of Defeat‘- What Francis Crick and Sydney Brenner taught Bob Goldstein about being scooped.

– An interesting article in Nature Jobs explores how scientists can use twitter to expand their social contacts and find jobs.

– The history of naming lab animals and is it a good idea, in Science.

– ‘What pushes scientists to lie?’- The Guardian discusses the STAP case and reproducibility in science.

– Graham Warren wrote an article on the importance of non-classic model systems, published in The Journal of Cell Biology.

– And American Scientist collated 75 reasons to become a scientist.

Weird & Wonderful:

– This stunning graphic shows how Darwin’s On the Origin of Species evolved over its 6 editions.

– Barbara Vreede announced to the lab that she was pregnant in an unusual way.

– What if Shakespeare had to apply for a science grant to write Hamlet? Here is what his proposal might have looked like.

– An article in PLOS Biology shows how to 3D print your lab equipment.

– If you are a cat (and science!) lover, you may like this:

Scientific research is sometimes like owning a cat. #science #phdproblems pic.twitter.com/D6MvhNlyMD

— TwistedDoodles (@twisteddoodles) February 26, 2015

Beautiful & Interesting images:

– This cool poster celebrates 16 amazing women in science.

– The Wellcome Trust announced the winners of their 2015 science image competition.

– Check out these beautiful hand cut paper microbes

– And finally, academic minions:  

Academic minions! :D pic.twitter.com/nuDQ0nMqVM — Dr Paul Coxon (@paulcoxon) February 20, 2015

Videos worth watching:

– Science out of the box is a great outreach project at the Johns Hopkins where scientists explain their research using a box of toys. Check out Erika Matunis explaining niche cells.

– “It’s almost unbelievable that before Darwin invented evolution in 1859 no one had ever evolved”- a parody documentary on evolution.

– And the Manchester Fly Facility released part 2 of their video series on why fly research is important. In this video- the hedgehog story:

Keep up with this and other content, including all Node posts and deadlines of coming meetings and jobs, by following the Node on Twitter

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Greetings from Chicago! My name is Kate Criswell and I am a graduate student at the University of Chicago, working with Dr. Mike Coates on axial column evolution and development in fishes. I just finished up a five-week visit, sponsored by the Development Travelling Fellowship, to the University of Cambridge to work with Dr. Andrew Gillis on skate axial patterning.

As a paleontologist by training, I am interested in using fossils to study ancestral conditions and independent evolution in the vertebral column. I began my PhD by examining a broad range of both extinct and extant fish skeletons, looking for similarities and differences in vertebral morphology and structure. After reconstructing ancestral conditions for vertebral characters on a phylogeny, I discovered that many components of the axial column complex, including vertebral centra, evolved independently numerous times in different groups of jawed vertebrates. My research has recently shifted to focus on development: I want to know if distinct lineages of fish (as well as tetrapods) use the same developmental mechanisms to build their vertebrae, and which of these mechanisms are conserved across all jawed vertebrates.

An example of a fossil shark, Xenacanthus (NMS 1891.41.6.B), with a preserved vertebral column.

Most of what we know about vertebral development comes from several well-studied vertebrate systems: chick, mouse, zebrafish, and medaka. Vertebrae typically form from a migration of sclerotomal cells that encircle the notochord and condense to form vertebral elements. Because most of the current knowledge on vertebral development comes from osteichthyans, or bony vertebrates, these taxa give an incomplete view of vertebral column evolution. I am focusing my research on chondrichthyans, or cartilaginous fishes, because they occupy a key phylogenetic position as the most proximate outgroup to osteichthyans and can provide an additional, crucial dataset. I am using the little skate, Leucoraja erinacea, to fate map the ventral part of the somite, to determine where in the vertebrae sclerotomal cells eventually end up, and to study the expression patterns of genes known to be involved in vertebral patterning.

I obtain little skate embryos from the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts. They are one of the fastest-developing chondrichthyans (~5 months from fertilization to hatching at summer temperatures!). The females lay two egg cases at a time, and will lay eggs year-round. To do the fate mapping experiments I cut windows in the egg cases and move the embryos to a petri dish, where I inject them with DiI. I then scoop them back up, deposit them back in the egg cases, and let them develop for two months.

While in Cambridge I learned several useful techniques: embedding and sectioning skate tissue to analyze data from somite fate mapping experiments that were started in the summer, staining with Haematoxylin and Eosin, and making probes and doing in situ hybridizations for several sclerotome markers. Because Andrew just recently began working at Cambridge, he didn’t have all of the necessary sectioning equipment set up yet. Luckily, I was able to use the microtome and vibratome in Dr. Clare Baker’s lab, which allowed me to meet and get to know even more wonderful scientists. This meant that I was dashing back and forth between the Zoology building and the department of Physiology, Development, and Neuroscience, but it was all worth it for the skills I learned.

Andrew and I in his lab in the Zoology building.

I used my weekends to explore some of the cultural aspects of Cambridge, visiting the Sedgwick Museum (earth sciences), the Fitzwilliam Museum (art and archaeology), and some of the beautiful colleges (King’s, Trinity, and St. John’s). I am very grateful for the opportunity to learn from such enthusiastic and knowledgeable scientists and really get to know a new city and university.

Just one of the lovely views of Cambridge – St. John’s College.

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Each year, the British Society for Developmental Biology (BSDB) awards the Beddington Medal to the best PhD thesis in developmental biology. The 2015 award went to John Robert Davis, who did his PhD with Brian Stramer at King’s College, London. We caught up with John at the BSCB/BSDB Spring meeting, where he gave a talk, and we asked him about his thesis work on contact inhibition, what he is doing now and his passion for comedy.

Congratulations on winning the Beddington Medal. What does this prize mean to you?

It is a huge honour! One of the first meetings I ever attended was a BSCB/BSDB Spring conference like this one, where Helen Weaver won the Beddington Medal. I will always remember thinking ‘wow, what a great honour and privilege to be recognized in such a way’, especially at that conference which was attended by big names in developmental biology such as John Gurdon. To be this year’s winner is a huge honour, although also a bit surreal!

I guess it was also a chance for you to attend this meeting?

I have just changed labs since finishing my PhD, so going to conferences was not in the agenda. So being invited to give the Beddington Medal talk gave me the opportunity to attend this meeting. It has been a great conference so far. I had the chance to chat with many people and it was amazing to hear Lewis Wolpert speaking last night.

Can you tell us a about your thesis work?

I worked with Drosophila hemocytes, trying to understand how they are able to form a characteristic 3 line pattern in the embryo. Hemocytes undergo a phenomenon known as contact inhibition, in which the migrating cells come into contact and then repel each other. I wanted to know whether contact inhibition could be driving this embryonic pattern. We developed a mathematical model to look at this question and found that contact inhibition was driving the emergence of this pattern. However, that could only be the case if collisions happened in a very specific way. So I spent the remainder of my PhD looking at how contact inhibition could be regulated and if it was as tightly controlled as it needed to be. I eventually focused on the actin cytoskeleton, which seemed to be playing a huge role in this process. We studied the role of actin during collisions and saw that as cells come into contact they play a cellular game of tug of war, pulling against each other. This seems to allow them to control their repulsion, and to form this evenly disperse 3 line embryonic pattern.

Why did you use Drosophila hemocytes as a system in which to study contact inhibition?

These cells are absolutely beautiful and easy to image in vivo. In addition, unlike other systems of contact inhibition like neural crest, where cells can maintain contacts and move as an epithelial sheet, hemocytes like to be by themselves. They don’t like to stay in contact with other cells for a prolonged period of time. This means that when you examine collisions you are only looking at two cells at a time, which simplifies the analysis and makes it easier to interpret. Finally, the power of Drosophila genetics allows us to quite easily manipulate the proteins that could be involved in this process.

So a versatile system.

Versatile, yes, and they are beautiful as well. The most beautiful cell type I have ever seen! You could be making a movie on the microscope and a visitor to the lab would have a look and be amazed: ‘Wow, you can see these cells move in real time’! It was a privilege working with them.

You mentioned how you created a mathematical model to examine how contact inhibition could explain the pattern generated by the hemocyte migration. Did you have to collaborate with mathematicians to generate this model? What do you think is the value of such interdisciplinary collaborations and what are the challenges involved in a successful collaboration of this nature?

None of the work that I did during my PhD would have been possible without working with mathematicians and engineers. It is a bit daunting at times, but I was very fortunate that there was another PhD student in the lab, Andrei Luchici, who is really good at explaining mathematical concepts. We used to have weekly maths sessions where he would explain things to us! I think this was very important. You hear stories about people who work with theoreticians and don’t have a clue what they are doing. I think it is important for them to just sit down with pen and paper and go through it and try to understand it. It is very rewarding. I feel that it is has helped me have an understanding of how things can possibly be working in Biology. It was a great honour, and good fun as well.

So in the future you won’t avoid collaborating with people in different fields…

No, I won’t avoid it. In fact, as part of the postdoc I have just started I will be working with more mathematicians and theoreticians. I think I’m always going to be next to a theoretician!

You mentioned how you worked out one mechanism by which contact inhibition could be regulated and controlled. Do you think that this mechanism, and indeed contact inhibition, plays a part in cell motility in other in vivo systems?

A recent paper modeled the patterning of cajal-retzius neurons in the same way that we did with Drosophila hemocytes, and reached very similar conclusions. It will be interesting to see if the mechanism that is at work in hemocytes is also involved in neuronal cells. Contact inhibition was first studied by Michael Abercrombie in fibroblasts back in the 50s, and a lot of the behaviours that we observe in hemocytes are also observed in fibroblasts. So a similar mechanism may also be occurring in fibroblasts. It could be a general process, but there is still a lot of work to do in other cell types to understand the role of actin in those collisions.

You mentioned that you are now doing a postdoc. Can you tell us a little bit what you are working on at the moment?

Im working in the lab of Nic Tapon, at the Crick Institute, looking at the mechanical regulation of the Hipo pathway, or Yorkie activity. We are examining Drosophila abdomen development, looking at histoblast proliferation and growth arrest during this process. It is early days but very exciting, and it involves more mechanics.

I hear you have a sideline as a comedian. Do you talk about science in your comedy?

Yeah, I have been doing comedy for many years, mainly improvised comedy and sketches. My writing partner has a physics PhD so our humour is very science related, and our jokes are somewhat geeky! But something I have recently been involved in which is a great way that comedy and science have come together is a show called The Wunderkammer. There is an improv group called ‘Do not adjust your stage’, and they do this show where they ask experts to talk about their fields (Biology, Physics, etc) and then create a whole show just based on that person’s research. I have been involved with them a few times and it has been really good fun, and the public loves it.

Do you have any advice for new PhD students?

I think my PhD was successful because of the people I worked with. I had a great supervisor and worked with some fantastic people that were always nurturing and helping me at various stages. So my advice is that you should try to find people to mentor you and help you. It is difficult to know in advance if your supervisor will be good or bad, but try to find other people in your department that will help you.

(2 votes)

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An experienced and meticulous Research Assistant is required to the join the Cardiovascular Development, Repair and Regeneration group led by Professor Paul Riley (in collaboration with Professor Tatjana Sauka-Spengler). The post is ideally suited for a candidate with an interest in developing a career that involves working at the interface of Developmental Biology and Regenerative Medicine, with a strong background in the former.

The Research Assistant will support work on deciphering the cellular and molecular mechanisms involved in the regenerating epicardium of the adult zebrafish heart, using a range of different techniques including CRISPR/Cas9 technology, Nanostring analysis, in situ hybridisation and multiplex hybridization chain reaction, tissue cryosectioning, immunofluorescence microscopy. Microinjection of zebrafish embyros, cell sorting, and management of wild type and genetically modified zebrafish lines.

You will have a first degree in biological or biomedical sciences, previous laboratory experience, with particular emphasis on embryology and advanced molecular biology methods. You will be organized and enthusiastic, demonstrating a high level of commitment to the work.

The position is funded by the British Heart Foundation, to cover maternity leave. It is available from 1 June 2015 until 31 January 2016.

The closing date for applications is noon on Wednesday, 6 May 2015. Interviews will be held on Thursday, 14 May 2015.

For more information and further particulars, please visit:

http://www.nature.com/naturejobs/science/jobs/519765-research-assistant-in-developmental-and-regenerative-medicine-maternity-cover

https://www.recruit.ox.ac.uk/pls/hrisliverecruit/erq_jobspec_version_4.display_form

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