Understanding images: Under the skin of PLOS Genetics’ October issue image

This is the first installment in a new series of blog posts from PLOS Genetics about our monthly issue images. Ian Smyth and Tia DiTommaso talk about October’s image from their article, DiTommaso et al.

Authors: Ian Smyth and Tia DiTommaso  (Monash University, Australia)

Competing interests: Ian Smyth and Tia DiTommaso  are authors of the two papers discussed in this blog.


Image credit: Tia DiTommaso

The skin is the body’s largest organ and it is exquisitely adapted to support life in the harsh, gaseous, terrestrial environment in which we live.  One of its principal roles is to maintain “barrier function” – in essence preventing “bad” things from entering your body (bacteria, chemicals etc.) and ensuring the good things (like water) are retained.  It also has important functions in repair (wound healing), thermoregulation and in providing a front line in immune surveillance. A particular feature of skin is its regional specialization to form structures like hair follicles and secretory sebaceous glands, both of which are featured on this month’s cover.  In this issue of PLOS Genetics, we describe the application of a “reverse genetics” screening approach to identify new genes which play important roles in maintaining the normal function of the skin.

Since the skin comprises most of the surface of the body it is supremely accessible, making it an attractive organ in which to assess gene function in experimental models.  Doing so in the mouse is particularly relevant for understanding human disease, because of the genetic and physiological similarity between the two organisms.  We took a high throughput approach to assessing gene function in the skin; systematically inactivating genes in mice and then asking what effect this had on skin development and structure.  In total examining the potential contributions of more than 500 genes to skin biology, identifying many novel factors that were important for different skin functions [1].

One such gene, Keratin76 (Krt76), seemed to play a particularly important role in skin biology.  The keratins encode a large family of proteins which form networks in the cells of epithelial organs (like the skin) and which contribute greatly to their structural integrity.  It was found that Keratin76 was required both for the normal process of wound healing and to maintain the waterproofing “barrier” function of the skin.  Interestingly, neither of these features seemed to be associated with a role for Keratin76 in maintaining structural stability, because cell lysis or tissue blistering was not evident in mice lacking the gene.  Instead, defects were described in the function of structures called “tight junctions”; microscopic connections which form a seal between neighboring skin cells. To understand this finding better, they examined whether the proteins which normally assemble to form the tight junction were present in cells lacking Keratin76.   Strikingly, one of the principal protein components of the tight junction, Claudin 1, was mislocalised. The normal localization of Claudin1 is shown in the featured image, where it is found on the surface of skin cells in the normal hair follicle.  Images of this type were key to highlighting a possible link between Keratin76 and Claudin1 and they provided the starting point for molecular studies confirming that the two proteins were physically as well as functionally associated.  Our paper therefore proposes that Keratin76 contributes to normal tight junction function by ensuring that Claudin1 localises appropriately to the structure [2].

These studies are important for a number of reasons.  Firstly, they highlight the potential for large scale “reverse genetic screens” in mice to identify new genes important for the biology of different organs. Secondly, they provide one of the first descriptions of an association between keratins and tight junctions themselves.  Finally, they challenge the historical view that keratins are simply structural scaffolds, in so doing adding to an emerging body of research which indicates a much more active role in the biology of the cell. Although considerable work remains to elucidate the mode of action of Keratin76 (and indeed the many other genes identified in the screen), this work establishes important precedents for our understanding of the biology of your largest organ.

1.             DiTommaso T, et al. (2014) Identification of genes important for cutaneous function revealed by a large scale reverse genetic screen in the mouse. PLoS Genetics 10(10):e1004705. doi:10.1371/journal.pgen.1004705

2.             DiTommaso T, et al. (2014) Keratin 76 is required for tight junction function and maintenance of the skin barrier. PLoS Genetics 10(10):e1004706. doi:10.1371/journal.pgen.1004706

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Protein structure prediction, pleiotropic patterns, and more: the PLOS Comp Biol October Issue

Here are our highlights from October’s PLOS Computational Biology.

Proteins execute many functions in the cell, and these biological functions are strongly linked to their three-dimensional structure. By constructing a probabilistic model for sequence variability, Erik Aurell and colleagues present an advance in how to predict protein structure in three-dimensional space. In the paper “Improving Contact Prediction along Three Dimensions”, the authors highlight that it is possible to improve along the second dimension by going beyond the pair-wise Potts models from statistical physics, which have so far been the focus of the field.

Rendering of complete dendritic morphologies for 2770 generated granule cells from the center 20 µm of the model dentate gyrus. Image credit: Calvin James Schneider

Rendering of complete dendritic morphologies for 2770 generated granule cells from the center 20 µm of the model dentate gyrus. Image credit: Calvin James Schneider

Pleiotropy refers to a phenomenon in which a single genetic locus affects two or more phenotypic traits. The study of pleiotropy is useful in gene function discovery and in the study of the evolution of a gene. In “Canonical Correlation Analysis for Gene-Based Pleiotropy Discovery”, Jose Seoane and colleagues present a new methodology, based on Canonical Correlation Analysis, for multiple association testing with high dimensional datasets. In applying the methodology to a genotype dataset and a set of cardiovascular related phenotypes, the authors discovered a new association between gene NRG1 and phenotypes related with left ventricular hypertrophy. The methodology can also be used to find pleiotropic patterns or multiple associations in other omics datasets.

Genome-scale metabolic models provide a powerful means of harnessing information from genomes to deepen biological insights. However, manually constructing accurate metabolic networks is a difficult task, and computational algorithms that rely on network topology-based approaches can result in solutions that are inconsistent with existing genomic data. Nathan Price and colleagues have developed an algorithm that directly incorporates genomic evidence into the decision-making process for gap-filling reactions. This algorithm both maximizes the consistency of gap-filled reactions with available genomic data and identifies candidate genes for gap-filled reactions.

Many protein-protein interactions (PPIs) are compelling targets for drug discovery. Disrupting the interaction between two large proteins requires forming a high affinity binding site that can bind both peptides and non-peptide drug-like compounds. Through a comparison of ligand-free and ligand-bound structures, Sandor Vajda and colleagues examine the mechanism of binding site formation in the interface region of proteins that are PPI disruption targets. The measures used for structure comparison are based on binding hot spots, regions that are major contributors to the binding free energy. The results provide insight on the origin of sites that can bind small molecules in protein-protein interfaces.

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This week in PLOS Biology

In PLOS Biology this week, you can read research articles about the regulation of glial cell activation, zinc regulation in E. coli and a new regulator of Wg/Wnt signalling. Also read articles from our magazine section on parasite tolerance, informal science education and genomic privacy.


A Tailored Response to Damaged Nerves

Image credit: pbio.1001985

Image credit: pbio.1001985

Glial cells are extremely sensitive to disruptions in the central nervous system. When axons are damaged, glial cells are activated and engulf the axonal debris. In a new research paper, Johnna Doherty, Marc Freeman and colleagues identify (in Drosophila) two novel regulators for Draper – the cell membrane receptor in glia that controls engulfment. First, PI3K signalling sets the baseline levels of Draper, and second, the transcription factor stat92E forms a novel auto-regulatory loop, allowing the level of activation to match the degree of damage incurred.


How to Live with the Enemy: Understanding Tolerance to Parasites


Image credit: Flickr user CaptainOates

A new Primer by Lars Råberg brings together the findings of three research articles recently published in PLOS Biology on the subject of tolerance to parasites. All three of these studies address our understanding of the causes and consequences of variation in tolerance. In a study of HIV in humans, Regoes et al. show that an MHC class I gene affects not only resistance (as previously known) but also tolerance. In a study of voles, Jackson et al. identify a transcription factor mediating age differences in tolerance to macroparasites. Finally, Hayward et al. demonstrate that tolerance to intestinal parasites in sheep is under positive directional selection, but that most of the variation is environmentally induced rather than heritable. These studies increase our knowledge of the genetic and physiological sources of variation in tolerance, and how this variation affects Darwinian fitness.


Redefining Genomic Privacy: Trust and Empowerment


Image credit: Duncan Hull

Fulfilling the promise of the genetic revolution requires the analysis of large datasets containing information from thousands to millions of participants. Current models of protecting human subjects create a zero-sum game of privacy versus data utility. Yaniv Erlich, Robert Kain and colleagues, propose the use of techniques that facilitate trust between researchers and participants. This article is part of a PLOS Biology collectionPublic Engagement in Science. Browse the collection here.


An Exquisite Nose for Zinc

O'Halloran (14-02860) Striking Image

Image credit: pbio.1001987

Zinc is an essential nutrient for most organisms, with the Zn2+ ion performing numerous structural and catalytic roles in a range of proteins. However, like many nutrients, organisms need to be able to maintain steady levels of zinc in the face of near-zero environmental or excessively high concentrations. In their new paper, Benjamin Gilston, Thomas O’Halloran and colleagues look at how the bacterium E. coli does this, by examining the structure and function of Zur, a transcriptional repressor that is sensitive to Zn2+ concentration. They show how Zur binds to DNA – two molecules of Zur, each binding two Zn2+ ions (three in some species), grip adjacent sites from opposite sides of the DNA strand.


Informal Science Education: Lifelong, Life-Wide, Life-Deep

Grand Canyon Trail of Time - Supergroup stromatolite - 0368

Image credit: Erin Whitakker

The words ‘‘science education’’ once evoked images of a professor in a white coat lecturing at a blackboard filled with equations or students in a lab conducting ‘‘experiments’’ with beakers and Bunsen burners. Such limited views of science education no longer hold today, when science, technology, engineering, and math (STEM) learning takes place in a wide variety of social dynamics and settings. In their new Community Page, Kalie Sacco, John Falk and James Bell discuss how informal science education cultivates diverse opportunities for lifelong learning outside of formal classroom settings, from museums to online media, often with the help of practicing scientists.


Armless – A New Shield for Armadillo

The Wg/Wnt signaling pathway, found in most animals, is essential for regulating tissue growth and the formation of different cell types during development. Defects in the Wg/Wnt signaling relay can have serious consequences, from aberrant organ patterning to malignant tumor formation. Gerlinde Reim, Konrad Basler and colleagues have identified a regulator of this pathway in Drosophila – the Armless protein, which acts as a positive regulator of Wg/Wnt signalling by interacting with the AAA-ATPase Ter94 and thereby protecting Armadillo/β-Catenin from being tagged for degradation.



Category: Biology, Cell biology, Cell signalling, Data, Developmental biology, Disease, Ecology, Education, Genomics, Infectious disease, Microbiology, Neuroscience, PLOS Biology | 1 Comment

This week in PLOS Biology

In PLOS Biology this week, you can read about access to research data, regulation of cell asymmetry and septum formation in Caulobacter, and unfolding and refolding RNA.


Access to Data – The Publishers’ Role


Image credit: pbio.1001779

A new community perspective piece by Jennifer Lin and Carly Strasser calls on publishers to promote and contribute to increasing access to data. This call to action emerged from a summit attended by data experts from diverse stakeholder groups; the Perspective outlines eight recommendations and a set of suggested action items for publishers to enhance access to data.


***Two-for-One Offer on Caulobacter Papers!!!


1. Stopping Cell Division in Case of Damage

Cells have evolved sophisticated mechanisms for repairing their DNA and maintaining genome integrity. A critical aspect of this process is the arrest of cell cycle progression until the genome has been repaired. In new research, Joshua Modell, Michael Laub and colleagues explore the mechanisms behind inhibition of cell division in the bacterium Caulobacter crescentus. They report a new mechanism, in addition to the previously known ‘SOS response,’ which involves the inhibition of division septum formation by DidA. Read more in the accompanying Synopsis.


2. Reversal of Fortune: Flipping a Kinase

Sharipo 1

Image credit: pbio.1001979

A fundamental strategy of asymmetric cell division is to place different signalling molecules in each nascent daughter cell, which then go on to drive the two cells toward different fates. In Caulobacter crescentus, a bacterial model used to study this process, a critical molecular driver is a “response regulator” protein called DivK, which interacts with pseudo-histidine kinase called DivL. Normally, information flows from histidine kinases, which transfer a phosphate signal to their response regulator; however in this issue of PLOS Biology, Seth Childers, Qingping Xu, Lucy Shapiro, and colleagues show that DivL has taken an unusual evolutionary twist that allows it to serve as a highly specific sensor for the phosphorylation state of DivK, thereby reversing the normal flow of information. Read more in the accompanying Synopsis.




Unfolding and Refolding RNA


Image credit: pbio.1001981

RNAs function in many essential cellular processes, often requiring them to form a specific three-dimensional structure. However they also have a propensity to become trapped in non-functional, misfolded structures. DEAD-box proteins are known to help by disrupting such misfolded structures. In a new research article, Cynthia Pan, Rick Russell and colleagues reveal how DEAD-box proteins capture transiently exposed RNA helices, preventing any tertiary contacts from reforming and potentially destabilizing the global RNA architecture. Helix unwinding by the DEAD-box protein then allows the product RNA strands to form new contacts. Read more in the accompanying Synopsis.


Category: Advocacy, Biology, Cell signalling, Data, Microbiology, Molecular biology, PLOS Biology | Leave a comment

This week in PLOS Biology

In PLOS Biology this week, you can read about managing disease outbreaks, alpha band oscillations, human embalming techniques, unexpected effects of synaptic size and staying asleep.


Controlling Disease Outbreaks Adaptively

Disease outbreak management is a highly relevant topic given the current Ebola outbreak in West Africa. In a new research article, Katriona Shea, Matthew Ferrari and colleagues present an ‘adaptive management’ approach. This model allows initial uncertainties to be acknowledged, but builds in knowledge gained during an outbreak to update ongoing interventions. They apply the model to two past outbreaks – foot-and-mouth in the UK and a 2010 measles outbreak in Malawi. They argue that in both cases, using adaptive management could have reduced costs or cases of disease, respectively.


Filtering the Outside World

Jensen 14-01746 (2)

Image credit: pbio.1001965

In order to filter only relevant sensory information from our environment, we rely on powerful mechanisms in the brain. Johanna Zumer, Ole Jensen and colleagues used electroencephalography and fMRI to test the role of alpha band oscillations in the occipital lobe in acting as a filter for irrelevant information. Their results suggest that alpha band oscillations are indeed involved as a gating mechanism in routing attended information downstream to other regions of the brain.





From “Silent Teachers” to Models

Eisma Credit Emmanouil Kapazoglou (2)

Image credit: Emmanouil Kapazoglou

Embalmed cadavers are an invaluable tool for medical teaching; indeed, they’re how many medical students get their first experience of real human anatomy. Preservation is necessary to bridge the gap between death and use, but the traditional formaldehyde method is limited in its usefulness. In a new essay by Roos Eisma and Tracey Wilkinson, the authors describe the method developed by W. Thiel. Where this method is available, it results in more flexible, realistic cadaver models with many uses – from surgical training to testing new equipment and techniques.


Synapses – Size Matters!

The process of neurotransmission involves the conversion of electrical signals into the release of a chemical neurotransmitter from a neuron’s synaptic terminal. In a new research article, Tom Baden, Anton Nikolaev, Leon Lagnado and colleagues worked on the synaptic terminals of bipolar cells in the zebrafish retina. Using a variety of techniques, they discovered that the physical property of synapse volume affected neurotransmitter release. Large synapses were slow and small synapses were fast. You can read more about this research area in the accompanying Primer.


The Neurobiology of Staying Asleep


Image credit: pbio.1001974

The fruit fly Drosophila melanogaster has become a key model organism for sleep research. Previously, a seminal fluid protein, Sex Peptide (SP), has been shown to act via the Sex Peptide Receptor (SPR) to reduce the daytime “siesta” sleep of females after mating. Yangkyun Oh, Sung-Eun Yoon, Young-Joon Kim and colleagues investigated the role of SPR in sleep regulation in Drosophila further, finding that another ligand of SPR, called MIP, is required for stable sleep in both sexes. MIP does this by acting via SPR to silence specific neurons that otherwise keep flies awake.


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Chromatin and Epigenetics: From Omics to Single Cells

As part of its mission to encourage engagement within the genetics community, PLOS Genetics is sponsoring a number of conferences and meetings this year. In order to raise awareness about these conferences and the researchers who attend them we are featuring a number of these conferences on Biologue.

At the Chromatin and Epigenetics Conference, which took place in Strasbourg, France, on the 14th and 15th of October, PLOS awarded a student travel award to Paul Fields. Paul talks about his experiences at the conference, the topics discussed and the beauty of Strasbourg.

Few conferences are able to blend the beauty and history of old Europe with cutting-edge science from around the world, but that is exactly what Abcam achieved with their “Chromatin and Epigenetics: From Omics to Single Cells” meeting in Strasbourg, France.  Robert Schneider and Maria Elena Torres-Padilla put together a fantastic lineup of speakers from all over Europe and the United States, creating a very exciting meeting with highly relevant topics.  While the conference was aptly titled “From Omics to Single Cells”, it could just as easily have been called Omics AND Single Cells.  It was clear from early on that a common theme throughout the conference would be the integration of these two concepts to produce insights into the nature of chromatin and epigenetic regulation and how this contributes to cell state regulation.


The picturesque cathedral in the center of Strasbourg. Image credit: Paul Fields

I got into Strasbourg the night before the conference and was only able to see a little of the beauty of the town before the start.  I managed to sneak in some of the wonders of Strasbourg over the few days I was here, including the picturesque cathedral in the center of town.  Day one of the conference was loosely centered on the omics perspective, including a variety of new methods to identify and characterize DNA methylation and its various intermediates.  Already in the second talk of the conference Sebastian Smallwood blended the omics and the single cell, presenting a fascinating method to address single cell heterogeneity in DNA methylation using single cell bisulfite sequencing.  Another recurring theme of the first day, which would carry over into the second day, was understanding chromatin and chromosomal structures within the cell.  Both Wouter de Laat and Susan Gasser presented new insights into our understanding of the feedback between chromosomal positioning and silencing/heterochromatin using two very different systems and approaches.  The end of day one was headlined by keynote speaker John Gurdon, who presented new work into understanding why some cells resist the process of cellular reprogramming.  Along with this he demonstrated just how far and how rapidly our understanding of cellular regulation from a chromatin perspective has come.   The day finished up with a fantastic French dinner; lots of food and a surplus of wine, as well as great conversations about the topics of the day.


The conference venue: the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France. Image credit: Paul Fields

Day two began, as people straggled in after a long night of dancing, with the focus shifting towards single cells.  Bas van Steensel led off the day.  He was probably one of the most cited speakers of the conference, for his pioneering work into understand nuclear lamin interactions.  He has now pushed our understanding of nuclear lamin interactions to the single cell level.  Following in the vein of creative approaches, many of the speakers across the day presented new adaptations of old methodologies to address questions at a single cell level.  As Alex van Oudenaarden said, just because you don’t think it will work, doesn’t mean it’s not worth trying. His group was able to adapt TriZOL-based methods to generate single cell RNA-sequencing.  From that approach they could then try to identify rare cell types, integrating both novel sequencing methods as well as new approaches to computationally handle outliers.  One of the more humorous moments of the day was Peter Fraser’s analogy for why we need to study single cells, comparing a panel of Wayne Rooney’s various expressions to a population of cells. If averaged across, only the most defining features stand out, his ears, ignoring the intricacies of the individual moments.  Tony Kouzarides was the second keynote speaker. His long ties to both Robert Schneider and Maria Elena Torres-Padilla provided humorous introductions and his body of work has dramatically broadened our understanding of chromatin mechanisms.  Furthering the topic of taking both omics and single cell readouts to a functional level, Brad Bernstein proved an appropriate final speaker, as his work on both histone modifications and single cell analysis of transcription across cancers provides a model for how this work can be used therapeutically to treat patients.

One of the great things about getting so many fascinating speakers into one conference is it becomes easy to see how researchers continue to feed off of each other, and in turn benefit from a wide range of expertise.  Across the speakers (and also in the posters) at this conference, approaches ranged from genetic to biochemical to biophysical and everywhere in between, yet all having a similar goal to better understand the mechanisms of chromatin and epigenetics.  As the problems become more difficult it will take a host of new integrated approaches to continue to solve these questions and apply them outside of the lab.  In closing, I would like to thank Abcam and PLOS for the opportunity to experience this conference in person, and visit the beautiful city of Strasbourg.


Category: Biology, Community, Conference, Education, Epigenetics, Genetics, PLOS Genetics, Research | Leave a comment

Melanoma Cells: A Fatal Attraction to LPA

Credit: Flickr user Phil Whitehouse.

A beautiful day, but what’s happening under the surface? Credit: Flickr user Phil Whitehouse.

A hot day, blue sky and an even bluer sea. A perfect day to spend on the beach. But while our skin is sizzling, very few of us are aware of what some of our cells might be up to. Melanoma cells could be busy dividing and trying to escape the skin in search of a blood vessel through which to colonize other parts of our body. But how do they decide it’s time to migrate from the skin? Is there some sort of “go” signal that makes them leave their safe haven and cause havoc elsewhere?


Andrew Muinonen-Martin and researchers from the Beatson Institute at the University of Glasgow led by Robert Insall have been busy trying to find a way to stop this aggressive cancer spreading. In a new article just published in PLOS Biology, they tell us about a very promising breakthrough in their search for this “go” signal that could be disrupted to prevent metastasis of these tumors.


Why should we worry if we suddenly realize that we have a strange mole growing in our skin at an alarming pace? Melanocytes (a specialised skin cell) produce a pigment called melanin whenever we are exposed to sunlight – this is what gives us the highly desired tanned look. However these melanocytes aren’t born in the skin, but in a far-away developmental tissue called the neural crest; their long migration to the skin where they can protect us against UV light means that they’re naturally good ‘runners’.


Credit: doi:10.1371/journal.pbio.1001966

Credit: doi:10.1371/journal.pbio.1001966

As we well know, these guardians of our skin can occasionally turn nasty – when a dangerous mutation occurs that transform them in cancer cells, they start proliferating horizontally within the skin. This would be unpleasant if it remained confined to the skin, but then something happens that make these cells to migrate downwards instead until they manage to escape into the body. This is the dreaded phase of melanoma: within weeks these highly mobile cancer cells can spread all around the body, with disastrous and often lethal consequences.


Insall, Muinonen-Martin and colleagues focus their research on chemotaxis – chemical cues that attract and direct cells’ movements – and they set up to try to identify a potential signal that might be triggering the melanoma cells’ deadly migration. They tested the effect of several known chemoattractants by closely watching the migration of melanoma cells in direct-viewing chambers that they previously developed. They found that lysophosphatidic acid (LPA), a fatty chemical common in human tissues – and in the serum used in cell culture medium – was able to attract these cells particularly efficiently. But in order to attract cells, a chemoattractant needs to be present in the form of a gradient so that cells can move from a region with less of the chemical to areas where it is more abundant. How is a potential LPA gradient formed in these tumors?


Watch this video of melanoma cells swarming from an area of low LPA – on the left -  to an area of high LPA – on the right (credit: doi:10.1371/journal.pbio.1001966):



The team analyzed the culture medium from groups of melanoma cells with different densities and saw that the cells were effectively breaking down the LPA molecules nearest to them. The result is a self-generated LPA gradient; low where cells have grown a lot – for example a tumour – and high away from the tumour where there are no melanoma cells. The researchers then looked closely at the more realistic ‘in vivo’ scenario in real tumours from mutant mice that are susceptible to melanoma. They took biopsies from different areas around the tumour, and use mass spectrometry to measure LPA levels. Again, this revealed an outward gradient. Cells located close to the center of the tumour were exposed to low levels of LPA, whereas cells at the edges of the tumour had access to much higher levels. Inevitably, this gradient seems to attract melanoma cells out of the tumour, following the scent of LPA and blazing a trail outwards, perhaps to a handy blood vessel.


LPA - the fatal attractant.

LPA – the fatal attractant.

The conclusion is, therefore, that the melanoma generates the signal for its own metastasis. But the researchers’ identification of the bearer of this signal leaves a door open for hope. If we can manage to stop LPA gradients being generated in the tumor –perhaps by inhibiting the enzyme that breaks LPA down – metastasis of these cells might become preventable. In the meanwhile, while a ray of hope shines in the sky, make sure you and your skin stay well protected with sunscreen.

Muinonen-Martin, A., Susanto, O., Zhang, Q., Smethurst, E., Faller, W., Veltman, D., Kalna, G., Lindsay, C., Bennett, D., Sansom, O., Herd, R., Jones, R., Machesky, L., Wakelam, M., Knecht, D., & Insall, R. (2014). Melanoma Cells Break Down LPA to Establish Local Gradients That Drive Chemotactic Dispersal PLoS Biology, 12 (10) DOI: 10.1371/journal.pbio.1001966

Category: Biology, Cancer, Cell signalling, Developmental biology, Disease, PLOS Biology | Leave a comment

This week in PLOS Biology

In PLOS Biology this week, you can read about moving lipids around the cell, good and bad autophagyhow skin cancer metastasises, and mending DNA replication forks safely.


 Moving Lipids from Organelle to Organelle

Prinz thumbMoving lipids and proteins from the endoplasmic reticulum to the mitochondria (and vice versa) is a vital process, but the mechanism of transfer which occurs when regions of these organelles are in close contact is not known. Sujoy Lahiri, William Prinz and colleagues used a genetic screen in Saccharomyces cerevisiae yeast to identify mutants with defects in lipid exchange. They then reported that a protein complex called EMC present in the endoplasmic reticulum is important for tethering it to mitochondria. They propose that the EMC interacts with the mitochondrial outer membrane complex TOM, placing the two organelles in close apposition and aiding the transfer of lipids. Failure to do this results in cell death, showing that the process is essential for life.


Autophagy: Making Sense of a Double-Edged Sword

Autophagy is the mechanism by which cellular material is delivered to lysosomes and degraded. The extensive literature on this process brings us to the conclusion that sometimes it is good and sometimes it is bad. For example, there was a recent attempt to inhibit autophagy in a child with a brain tumour. So if we understood more about how autophagy impacts on health and disease, could we improve treatment and prevention? This is the question asked in a new Essay by Andrew Thorburn. He reviews our knowledge of autophagy and bacterial infection, cancer and cell death. He concludes that mechanistic understanding of biological processes will lead to practical applications, and that the current rapid pace of progress is encouraging.


Melanoma Cells: A Fatal Attraction for LPA

Credit: doi:10.1371/journal.pbio.1001966

Credit: doi:10.1371/journal.pbio.1001966

Melanoma is a highly metastatic and aggressive form of cancer. In a fascinating new study, Andrew Muinonen-Martin, Robert Insall and colleagues address what drives melanoma cells to start migrating out from the tumour – a poorly understood process. They focussed on the chemical signals that guide tumour cell migration. In both cell lines and in mice, they showed the importance of the breakdown of a lipid called lysophosphatidic acid (LPA). A gradient is created, with higher concentrations of LPA further away from the tumour, which acts as a chemoattractant, drawing tumour cells out into surrounding skin and blood vessels. These findings could have important implications for new treatment avenues for skin cancer. Read more in this blog post by Ines Alvarez-Garcia.


Reining in the Copy-Editors

Maintaining genetic fidelity is of paramount importance to living organisms. During DNA replication, obstacles to the progression of DNA replication forks can trigger repair by patching in the correct DNA sequence, using the second copy of that chromosome as a template – a process known as homologous recombination. However, use of the wrong template can result in genome rearrangements, such as those often observed in cancer and genomic disorders. Violena Pietrobon, Sarah Lambert and colleagues investigated how the delicate balance between insufficient and excessive homologous recombination is maintained, identifying an evolutionarily conserved interplay between CAF-1 (a chromatin assembly factor) and RecQ-type helicases that helps to maintain genome stability in the face of replication stress.


Category: Biology, Cancer, Cell biology, Cell signalling, Disease, Molecular biology, PLOS Biology | Leave a comment

Keep Calm and Evolve On

Lauren Richardson, Associate Editor for PLOS Biology, discusses a new paper published in the journal.

We generally think of evolution as a beneficial process, letting organisms adapt and excel in new and different environments. But as we all know, not all change is good. Deleterious mutations are common in natural populations, and often piggy-back on adaptive, beneficial mutations. When a harmful mutation crops up in the genome, restricting or altering an organism’s ability to function well, evolution must respond to restore the ideal condition. The main way this is done is through compensatory evolution, where the effects of detrimental mutations are compensated by other mutations elsewhere in the genome. In a recent study published in PLOS Biology, a group based in Szeged, Hungary, led by Csaba Pal, characterized – on a massive scale – how compensatory evolution is able to restore peace and harmony after a disruptive genomic event, gene loss.

Image Credit: Sarah Bissonnette.

Image Credit: Sarah Bissonnette.

Saccharomyces cerevisiae (baker’s yeast), in lab conditions, likes to double every one-and-a-half hours. You could practically set your watch to a happily growing culture. Deletion of certain genes, however, will slow yeast’s growth rate. Slow growth is a highly unfavorable state for a yeast, as it’s in direct competition with neighboring yeasts in a culture (or on a rotting apple). Slower growth means a higher chance of getting swamped out of a population. To combat this, compensatory evolution leads to additional mutations in the genome to restore fitness. But how does this process work?

Image Credit: Csaba Pal

Image Credit: Csaba Pal

Using the awesome power of yeast genetics, the authors characterized 180 slow-growing yeast strains, each one missing a single gene. Amazingly, they found that nearly 70% of the strains were able to improve their growth rate following laboratory evolution experiments. The authors grew the yeast for 400 generations, which, if these yeasts were humans with a 20-year generation time, would be roughly equivalent to 8000 years! The 180 missing genes covered a wide range of molecular processes, showing that evolution can solve almost any kind of genetic problem.

The authors did their studies in quadruplicate, meaning that for each gene deletion they grew four independent cultures. By sequencing the genomes of evolved strains, they found that, in general, each independent culture used different compensatory mutations to fix the same slow-growth problem. Interestingly, by comparing gene expression profiles, they found that the compensatory fix never restored the original state. Instead the yeast found new ways to regain optimal growth – a workaround instead of a faithful restoration. The effects of these diverse fixes were revealed when they grew the evolved strains in various stressful conditions – each independently evolved strain responded differently. This demonstrates how gene loss can “drive populations to new adaptive peaks,” and can make them potentially better or worse suited to a new environment.

And because all biological studies can be tied in to cancer biology (see anyone applying for postdoctoral funding), I should mention that gene loss events are frequent during tumorigenesis. From these studies you could hypothesize that a gene loss event early on in tumorigenesis could drive compensatory mutations that might promote an increased growth rate and adaptation to the completely crazy tumor microenvironment. But to yeast geneticists, their first thought is probably: what does this mean for the knock-out collections? It means you should probably freeze them down. FAST.



Szamecz, B., Boross, G., Kalapis, D., Kovács, K., Fekete, G., Farkas, Z., Lázár, V., Hrtyan, M., Kemmeren, P., Groot Koerkamp, M., Rutkai, E., Holstege, F., Papp, B., & Pál, C. (2014). The Genomic Landscape of Compensatory Evolution PLoS Biology, 12 (8) DOI: 10.1371/journal.pbio.1001935

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Pupil size and decision making, timing evolutionary innovation and understanding ATP allosteric functions: the PLOS Comp Biol September issue

Here’s our pick of the highlights from September’s PLOS Computational Biology.

The precision with which people make decisions can be predicted by measuring pupil size before they are presented with any information about the decision. According to Peter Murphy and colleagues, spontaneous, moment-to-moment fluctuations in pupil size can predict how a selection of participants varied in their successful decision making. A larger pupil size indicated poorer upcoming task performance, due to more variability in the decisions made once the relevant information was presented. The authors also found that certain individuals who had the largest pupils overall also tended to be the least consistent in their decisions.

Our September issue image: Matching drug binding pockets in protein models using sequence order-independent structure alignments. Image Credit: Michal Brylinski.

Our September issue image: Matching drug binding pockets in protein models using sequence order-independent structure alignments. Image Credit: Michal Brylinski.

Evolutionary adaptation can be described as a biased, stochastic walk of a population of sequences in a high dimensional sequence space. The population explores a fitness landscape and the mutation-selection process biases the population towards regions of higher fitness. Krishnendu Chatterjee and colleagues estimate the time scale that is needed for evolutionary innovation, using the length of the genetic sequence that needs to be adapted as their key parameter. The authors show that a variety of evolutionary processes take exponential time in sequence length, and propose a specific process, ‘regeneration processes’, which allows evolution to work on polynomial time scales. In this view, evolution can solve a problem efficiently if it has solved a similar problem already.

Endogenous adenosine-5’-triphosphate (ATP) can be regarded as a substrate and an allosteric modulator in cellular signal transduction. By analysing the properties of allosteric and substrate ATP-binding sites, Shaoyong Lu and colleagues found that the allosteric ATP-binding sites are less conserved than the substrate ATP-binding sites. Allosteric ATP molecules adopt both compact and extended conformations in the allosteric binding sites, while substrate ATP molecules adopt extended conformations in the substrate binding sites. The authors’ results provide an overall understanding of ATP allosteric functions responsible for regulation in biological systems.


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