the Miller Lab at the University of Washington

Every two years, researchers from all over the world that use worms as a model organism come together at UCLA for the International C. elegans meeting. This year several members of the Miller Lab made the trip down to LA for an awesome week of talking science, networking, and catching up on all the newest worm research tools. There was so much cool stuff to learn about it is hard to pick favorites, but read below to find out what Hannah and Emily thought was especially interesting this year:

Hannah Chapin, postdoc
As a newcomer to C. elegans it was eye-opening to be exposed to people studying such diverse aspects of the nematode’s existence.  From counting nematodes in rotting fruit (they live in the stems and flesh of very rotten apples, apparently) to studying the effects of parasites and infectious bacteria on nematode cells, the meeting gave me a context of the cells I study.  These are far from being cells in a petri dish, they’re cells in an organism with a complex and beautiful natural history.

I was intrigued by the presentation about the role of mitochondria in neurogeneration.  Randi Rawson from the Jorgensen Lab (abstract 72) described a way to force mitochondria out in to the axons of worms that otherwise have defective mitochondrial localization in neurons.  The presence of neurons was protective against degradation caused by severing the axon.  The dynein-based strategy for mitochondrial delivery was interesting, and raises questions about the effect that the presence – or absence of mitochondria – has on the surrounding cytoplasm.

An unexpectedly elegant presentation was given in the Cell Biology section by Shirin Bahmanyar (abstract 155).  Organelle identity is defined, in part, by the lipid composition of its membrane, but what determines lipid population is a more challenging question.  She described the localization of the enzyme that activates lipin-1 (http://www.ncbi.nlm.nih.gov/pubmed?term=bahmanyar,%20s%20lipid&cmd), thereby allowing the nuclear envelope to contain a lower percentage of PI and a higher amount of PC/PE.

Also in the cell biology session was an interesting discussion of how intracellular intestinal parasites hijack the apical recycling machinery to facilitate spore release from the apical surface, thereby sending the spore on its way to complete the fecal/oral replication cycle. (Suzy Szumowski from Emily Troemel’s lab, abstract 157).

Emily Fawcett, MCB Graduate Student with her OWN BLOG!
After each conference I attend, I post the Top 5 Highlights from the meeting onto my science blog, From Behind the Scope. To continue with that format, in no particular order, here are my top 5 highlights of WORM2013!

#1: The hot topic: chromatin remodeling during stress!

I remain a bit partial to this topic, as it is the focus of my own research, but I was extremely excited to see so many fabulous talks and posters focusing on the relationship between chromatin remodeling and stress response! In particular, Christian Riedel from Gary Ruvkun’s lab demonstrated that the SWI/SNF chromatin-remodeling complex is required for DAF-16 (FOXO) gene-activation, and ultimately DAF-16 dependent longevity. This work was recently published in Nature Cell Biology and can be found here. Excitingly, David Fay also described a role for SWI/SNF in stress response, as a mediator of the ethanol and stress-response element (ESRE) pathway. These talks, along with multiple posters (including mine!), really begin to illustrate the critical requirement for chromatin remodeling in a multitude of stress response pathways.

#2: Transdifferentiation… is awesome.

As a trainee in developmental biology, and after recently listening to John Gordun discussing the challenges in transdifferentiation at ISDB2013, Joel Rothman’s talk blew me away. While Gordun’s talk emphasized how removal of chromatin marks specific to differentiated cells is one of the most difficult aspects of transdifferentiation, Rothman described a phenomenon in worms in which this process is not even necessary!  Expressing a single transcription factor, elt-7, resulted in the conversion of differentiated pharynx into endoderm, even in the absence of cell division. This talk was definitely one of the “THAT IS SO COOL” moments of WORM2013 for me.

#3: Memorable talks about teeth, exercise, and sex.

Based on the conference twitter feed and the chatter buzzing about the crowd, the next 3 talks were some of the most memorable, as well as the most unique! Mary Ann Royal of the Driscoll lab showed that 30 minutes of swimming a day results in increased pharyngeal pumping later in life, suggesting that “exercising” has health benefits even in worms! Eric Ragsdale  of the Sommer lab wowed the crowd with a gruesome video of P. pacificus chowing down on an unsuspecting C. elegans. His talk then went on to focus on the genetic control of a developmental teeth dimorphism in P. pacificus by a sulfatase encoded by eud-1. Finally, Cheng Shi of the Murphy lab pointed out a phenomenon we all felt we should have noticed previously: N2 worms shrink up to 30% after mating! These animals, in addition to a reduction in size, also are less attractive to other males, and live shorter lives. As male seminal fluid contributes to this phenomenon, it may represent an example of male influence on hermaphrodites to maximize their own reproductive success. Overall, Mary Ann, Eric, and Cheng definitely win the “most memorable” superlatives of WORM2013.

#4: Disease models in C. elegans!

As a scientist working in model organisms, I am always excited to hear about disease models in C. elegans, as it is a great way to study the genetic basis of human disease. Susana Garcia from the Ruvkun lab introduced a worm model designed to investigate the toxicity of CUG repeat-containing RNA, which is commonly associated with the human disease myotonic dystrophy. Garcia discovered that the nonsense mediated decay pathway normally functions to clear these toxic repeats, suggesting that it may be a good target for future myotonic dystrophy research.

Emery-Dreifuss muscular dystrophy is due to mutation in the lamin protein. A.  Mattout from the Gasser lab demonstrated that this mutation, in worms, leads to failed tissue-specific release of heterochromatin and disrupted muscle function. By restoring chromatin organization through genetic manipulation, Mattout was able to fully rescue muscle function in these animals, suggesting that chromatin mislocalization may be of particular importance in human laminopathies.

#5: New insight into everyone’s favorite topic, insulin-like signaling!

It wouldn’t be a worm meeting without several dozen talks and posters about the FOXO transcription factor DAF-16. This year was no exception, but it was great to see some really remarkable new discoveries in a field that has garnered so much interest in the worm community! To highlight just a few, Adrianne Wolstenholme from the University of Bath demonstrated the discovery of the sole glutamate transporter in worms, FGT-1! Additionally, Ronald Tepper from the Bussemaker lab at Columbia gave a great talk on the identification of PQM-1, the main regulator of the class II growth and development genes originally thought to be directly activated by DAF-16.

As you can tell from the sheer number of talks I’ve mentioned, there was a huge amount of elegant science and interesting discoveries at WORM2013. Visit the meeting’s website for full abstracts and dates of future WORM events!

The Miller Lab’s recent research is the focus of a Science Spotlight feature! Matt Arnegard did a great job explaining the Dana’s recent publication in PLoS ONE, “HIF-1 and SKN-1 Coordinate the Transcriptional Response to Hydrogen Sulfide in Caenorhabditis elegans“.

Right now you have to be able to get into Center Net to read it. Matt tells me it will be open for the general public soon. I will update this page when that happens. In the mean time, I have pasted the text here:

Increased longevity in an extreme environment is orchestrated by hif-1 and skn-1

UPDATE: Here is a PDF file of the article that you can download and read. It even includes the super awesome worm picture!

December 12, 2011

Mice exposed to hydrogen sulfide exhibit lower metabolic rates and core body temperatures reminiscent of hibernation. Similarly, rats demonstrate increased survival following severe hemorrhage if they are first administered this same toxic compound at sub-lethal doses, inducing a state of suspended animation. The tantalizing possibility of placing humans into a similar state of sulfide-induced hibernation could have far-reaching future applications, including: slowing down a trauma patient’s metabolic clock as she or he is transported to intensive care; prolonging the health of donated organs prior to transplantation; and better protecting a cancer patient from the ill effects of radiation or chemotherapy targeted at a malignant tumor. In their earlier work on animal responses to hydrogen sulfide, Fred Hutchinson Cancer Research Center investigators Dr. Dana Miller and Dr. Mark Roth (Basic Sciences Division) first demonstrated life-prolonging effects in the simpler and genetically more tractable organism, Caenorhabditis elegans, shown in the accompanying photomicrograph. Akin to mammalian hibernation responses that delay death under severe environmental conditions, responses of this nematode worm to 50 parts per million hydrogen sulfide include increased heat tolerance and lifespan. The focus of these investigators on C. elegans is an attempt to better elucidate general molecular mechanisms underlying responses to sulfide, which remain obscure in more complicated mammalian models. Hutchinson Center researcher Mark Budde and principal investigator Roth also previously demonstrated that the transcription factor referred to as hypotoxia-inducible factor 1 (hif-1) is required for a nematode’s survival following exposure to hydrogen sulfide. Hif-1 is the nematode homologue of a conserved transcription factor known for its role in orchestrating mammalian responses to low oxygen concentrations.

A new paper first-author by Miller, who recently started her own lab group in the Biochemistry Department at the University of Washington, was aimed at broadly understanding the transcriptional responses of C. elegans to hydrogen sulfide using a DNA expression array and real-time quantitative PCR. Dr. Jeff Delrow (FHCRC DNA Array Facility) and Dr. Jerry Davison (FHCRC Computational Biology) contributed their expertise to the team’s microarray analyses. With the microarray dataset in hand, Miller et al. found that hydrogen sulfide induced rapid transcriptional changes to numerous genes. These responses appeared as early as 1 hour after initial exposure, and they increased further by 48 hours, the time required for C. elegans to develop into first-day adults and exhibit both increased lifespan and thermotolerance. Functional annotation of genes up-regulated during the response suggested that many of them are associated with protein homeostasis, including transcripts related to aging and stress resistance as well as those involved in protein turnover via the ubiquitin proteosome system. Comparing hydrogen sulfide exposure of hif-1 loss-of-function mutants to control animals, Miller and collaborators went on to show that hif-1 is essential for these transcriptional responses. Interestingly, there proved to be little overlap between transcriptional targets of hif-1 in environments high in hydrogen sulfide vs. low in oxygen. The authors also observed that many up-regulated genes were Sdz genes (so named for their skn-1 dependent zygotic expression), suggesting that sulfide-induced transcriptional changes are skn-1 dependent. By feeding their nematodes bacteria containing either a vector for small interfering RNA directed against skn-1 or an empty vector as a control, the investigators confirmed their hunch: skn-1 acts to both up- and down-regulate genes in response to hydrogen sulfide. As a final test of skn-1 function, the authors verified that skn-1 homozygous mutants failed to survive in a hydrogen sulfide environment in which hetrozygotes and wild type animals thrive. Protein homeostasis plays an increasingly appreciated role in aging, senescence and neurodegenerative disorders such as Alzheimer’s disease. The findings of Miller et al. suggest that, during adaptation to hydrogen sulfide in nematodes, skn-1 and hif-1 seem to work together to remodel the protein turnover machinery, which increases lifespan and thermotolerance of these worms via effects on protein homeostasis.

Miller DL, Budde MW, Roth MB. 2011. HIF-1 and SKN-1 coordinate the transcriptional response to hydrogen sulfide in Caenorhabditis elegans. PLoS ONE 6:e25476.

– ME Arnegard

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