Keystone Review



Keystone Symposium on DNA Methylation and Epigenomics – Zebrafish Highlights

March 29 – April 3, 2015

Brandon Kent
Graduate student, Sadler and Walsh laboratories, Icahn School of Medicine at Mount Sinai, USA

Heritable, covalent (“epigenetic”) modification of DNA and the core histone proteins is a central tenet vital to cellular specification, differentiation, and an organism’s development and survival. The join Keystone Symposium on DNA Methylation (http://www.keystonesymposia.org/15Z1) and Epigenomics (March 29th – April 3rd, 2015, Keystone CO) focused on providing the latest insights regarding epigenetic regulation of development, cancer, and application to advanced diagnostics and possible clinical application.

The zebrafish has emerged as a prominent model with regard to studying epigenetic regulation of early embryonic development. Research has been increasingly focused on epigenetic patterning of the zebrafish genome. This joint Keystone Symposium featured work from several prominent zebrafish laboratories.

Members of the Cairns group (University of Utah School of Medicine) presented work regarding epigenetic patterning of the zebrafish zygote to promote the formation of transcriptionally permissive, poised, and repressive domains across the genome in an effort to prime the embryo for proper zygotic genome activation. Work done by the Lister group at the University of Western Australia focused on the role of TET-family proteins in mediating DNA demethylation during development. The Sadler group presented their work on the epigenetic regulator, Uhrf1 and in two posters defined a critical role for this gene in in both the pre-gastrula embryo and at later developmental stages. Most exciting was a workshop previewing the Epigenome Browser (http://epigenomegateway.wustl.edu/browser/) designed by Ting Wang’s group at Washington University in St. Louis. In this comprehensive and user friendly portal to the epigenome, there are datasets of methylation and RNAseq analysis across early embryonic stages and from some adult tissue.

Critically, the zebrafish model system can be utilized to elucidate epigenetic mechanisms underlying embryonic development and cancer, especially in relation to human disease, that other model systems cannot provide. With regard to the high profile and impressive work presented at the Keystone Symposium, the benefits of in vivo modeling in the zebrafish were readily apparent and appreciated.

Zebrafish make their own sunscreen

Zebrafish make their own sunscreen

Osborn, R.A., Almabruk, K.H., Holzwarth, G., Asamizu, S., LaDu, J., Kean, K.M., Karplus, P.A., Tanguay, R.L., Bakalinsky, A.T., Mahmud, T. (2015). De novo synthesis of a sunscreen compound in vertebrates. eLIFE.

A compound known as gadusol is responsible for protecting many animals, like the zebrafish, from the sun’s harmful ultraviolet radiation, a new study from Oregon State University finds.

Researchers originally believed that the zebrafish obtained gadusol from eating algae, which has long been known to naturally produce the compound. As it turns out, many fish, amphibians, birds and reptiles seem to have developed the ability to produce gadusol through “natural genetic engineering”.

“The ability to make gadusol, which was first discovered in fish eggs, clearly has some evolutionary value to be found in so many species,” remarked study lead author Taifo Mahmud. “We know it provides UV-B protection, it makes a pretty good sunscreen. But there may also be roles it plays as an antioxidant, in stress response, embryonic development and other functions.”

Mahmud and his team also discovered a way to produce high volumes of gadusol from yeast, which could potentially be applied to commercial sunscreens. Mahmud also notes that ingestion of gadusol could possibly provide a sunscreen that protects the body from the inside.

More from Oregon State University: http://oregonstate.edu/ua/ncs/archives/2015/may/no-lotions-needed-many-animal-species-produce-their-own-sunscreen

Read full research here: http://elifesciences.org/content/elife/4/e05919.full.pdf

Murcia University honours Dr. Leonard Zon

Murcia University honours Dr. Leonard Zon

Jorge Galindo-Villegas, Murcia University, Spain

On April 21st, 2015, Dr. Len Zon, Director of the Stem Cell Program at Children’s Hospital Boston at Harvard Medical School (USA), was made Doctor Honoris Causa by Murcia University, Spain. The academic ceremony was presided over by the Honorable Rector Magnificus José Orihuela Calatayud and several distinguished members of the University community. The ceremony took place in the auditorium “Hermenegildo Lumeras de Castro” located beneath the Faculty of Chemistry which faces the Faculty of Biology, on the Espinardo campus. The ceremony, which was broadcast live, included the performance of different pieces by the chamber orchestra of Murcia University. Len’s promoter was Dr. Victoriano Mulero, Professor of the Department of Cell Biology and Histology, who gave the Laudatio speech.

The ceremony began with the entrance of the academic authorities to the sound of Andante, which was followed by the opening speech given by the Rector Orihuela Calatayud. The General Secretary of the University, Santiago M. Alvarez Carreño proceeded to read out the agreement made by the Board of Governors to the proposal made by the Department of Cell Biology and Histology, Faculty of Biology, to confer the Honoris Causa Degree on Dr. Zon. This agreement recognizes Len’s brilliant teaching, outstanding research track record and his renown as a leading pediatrician. He is one of the world leading figures in the field of stem cells transplantation, a researcher specialized in blood diseases and, quite importantly, founder of a new avenue of hematological research and drug screening to cure cancers, among many other diseases, using the zebrafish as a vertebrate animal model. After the agreement was pronounced, the Rector kindly asked for the presence of the Laureate. Len entered accompanied by his promoter Dr. Mulero and the Dean of the Faculty of Biology, Dr. Jose Meseguer, to the tune of Concerto for Two Trumpets in C Major (RV537). After everyone took their seat, Professor Mulero gave his Laudatio of Len in which he offered an extensive overview of his outstanding and brilliant academic career. Then, the Rector awarded Len with a Doctor Honoris Causa, thus becoming a member of the University’s Senate of Doctors. The last part of the act included the new Doctor’s speech of acceptance, following the rendering.

Len acknowledged the award, by immediately telling a funny phrase which made everyone in the audience lose the solemnity of the act with a big laugh: “I have had the opportunity of being twice in each of the three most important cities in Spain, twice in Madrid, twice in Barcelona and of course, twice in Murcia” (Murcia is a quite small town without touristic recognition). He continued by speaking a bit about his daily work. He presented himself as a hematologist by training, a medical doctor who takes care of children presenting blood diseases or cancer, and a researcher keen to learn and decipher the biology of stem cells to produce effective drugs to treat mortal human diseases.

In his speech, he stressed the several advantages displayed by the zebrafish as a vertebrate animal model. He then introduced his particular and interesting research focus by using a graphical video which he produced. The video showed a transgenic zebrafish embryo expressing fluorescence in the blood cells and he described how it was used to dissect the formation of these important cells in vertebrates. The impressive video came to a climax when he introduced how blood stem cells go into the circulation and eventually, to the intermediate cell mass at the tail where the blood cells are formed, following the process known as homing, which is accomplished through the interaction with endothelial and stromal cells in the vascular hematopoietic niche. After dividing again, they then go back into circulation and eventually will colonize the kidney. Some will go further to the thymus, allowing the animal to have blood for its entire lifetime. Len highlighted the functional importance of this process, where he transplanted stem blood cells allowing sick people to live an entire life-time. Proud of his findings he mentioned “I’ve done this procedure in a broad number of patients. Although we know how to make bone marrow transplantation, we don’t really understand how it works”.

To end his acceptance speech, Len mentioned that now his laboratory is interested in knowing more about the mechanism and pathways, using the zebrafish as a feasible live vertebrate model. So far, using thousands of small zebrafish embryos and a high-throughput chemical genetic screening, he has identified prostaglandins as stimulators of blood stem cell production both during embryogenesis and in adulthood. His studies may support a deeper comprehension of how human blood stem cells home to the marrow, engraft and self-renew, and suggest new therapeutic approaches for hematological disorders.

Spotlight on Zebrafish

Spotlight on Zebrafish: Translational Impact

Amatruda, J.F. Dhillon, P., Patton, E. and Ramakrishnan L. (2014) Spotlight on Zebrafish: Translational Impact. Dis. Model. Mech. 7, 731733


Read Full Article Here

In recent years, the zebrafish has emerged as an increasingly prominent model in biomedical research. To showcase the translational impact of the model across multiple disease areas, Disease Models & Mechanisms has compiled a Special Issue that includes thought-provoking reviews, original research reporting new and important insights into disease mechanisms, and novel resources that expand the zebrafish toolkit. This Editorial provides a summary of the issue’s contents, highlighting the diversity of zebrafish disease models and their clinical applications.

Zebrafish (Danio rerio) have fast made their way from pet stores and home aquaria into research laboratories worldwide. Their weekly matings produce 100 to 200 embryos that rapidly and synchronously march through embryonic development, so that within 5 days of fertilization, they are mature, feeding larvae. Zebrafish are small and inexpensive to maintain in high numbers, facilitating large-scale experimentation and cheap in vivo drug screens. Famously, the fish are transparent during early larval stages, allowing investigators to directly observe internal development and making the fish a favorite of developmental biologists since the 1960s. But in recent years, the utility of zebrafish has been proven beyond developmental fields, and they are now being found in more and more laboratories studying behavior, diabetes, heart disease, regeneration, stem cell biology—and cancer.

Critically, zebrafish can be used to identify the important pathways and processes that cause cancer in people. Common organ systems and cell types are shared between human and zebrafish, and whether induced by transgenesis or carcinogens, cancers arising from the blood (leukemia and lymphoma), pigmented cells of the skin (melanoma), and the cells that line the bile ducts (cholangiocarcinoma) have microscopic features that are essentially indistinguishable between humans and zebrafish.

One aim of a Disease Models & Mechanisms (DMM) ‘Special Issue’ is to highlight how emerging disease models can lead to exceptional growth in particular areas of translational research. This is especially true for this issue, Spotlight on Zebrafish: Translational Impact. The zebrafish has traditionally been used to study developmental biology. Its optical transparency for the first few weeks, high fecundity and ex vivo fertilization have meant that the fundamental processes and mechanisms of vertebrate embryo development from a single cell through to a swimming fish can be studied in exquisite detail. Over the past decade these same features have enabled the zebrafish to become a preeminent disease model and tool for studying disease mechanisms. Importantly, discoveries in zebrafish disease models are leading to new perspectives on human disease and new drugs that are entering the clinic in diverse areas from cancer to tuberculosis.

We are delighted to present an issue packed with reviews, research and resource articles from researchers at the cutting-edge of their respective disease area of interest. The issue also includes a compelling interview with Len Zon, pioneer in the zebrafish disease models community, and a unique poster representation of the translational applications of zebrafish research. Here, we summarize the contents of the issue, and give our views on what makes each article special.

Read Full Article Here