Alpine Marmot

Research highlights April - June 2019

In our research highlights series, representatives of our faculty select their most significant publications from the Crick each quarter.

Bentley lab

Underestimating the power of positive feedback

Positive feedback defines the timing, magnitude, and robustness of angiogenesis

Page et al., Cell Reports, 27, 3139-3151.e5 (2019)

Group leader Katie Bentley was a lead author of a study exploring the process of angiogenesis; the formation of new blood vessels in the body. By combining computational modelling with in vivo studies, the collaborative research with colleagues at the University of Manchester, Boston University, University of Uppsala, Harvard Medical School and King’s College London revealed a previously underappreciated role of positive feedback in the timing, magnitude and robustness of angiogenesis.

Gutierrez lab

New method reveals how antibiotics reach their targets

Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages

Greenwood et al., Science, 364, 1279-1282

Scientists developed a new imaging technique that allows them to see how a tuberculosis (TB) drug reaches its target inside the pathogens. The Crick-led team were able to use the technique to see that the TB drug, bedaquiline, forms small pools inside cells which gradually leak and kill the bacteria. Bedaquiline works because it doesn’t dissolve in water, something that was previously thought to be an undesirable feature of drugs. By seeing precisely how bedqauiline moves inside cells, the team have gained new insights which can be used to develop new antibiotics. 

Read the full news story.

Nurse lab

The relationship between cell size and nucleus size

Nuclear membrane protein Lem2 regulates nuclear size through membrane flow

Kume et al., Nature Communications, 10, 1871 (2019)

Paul Nurse’s group has been investigating how the size of the cell’s nucleus is determined. The size of the nucleus is proportional to the size of the cell for a range of cell types, but it is not clear how the nucleus’ size is set as the cell grows.

The team found that a protein in the membrane surrounding the nucleus called Lem2 appears to act as a valve between the nuclear envelope membrane and the other parts of the cellular membrane system called organelles. They suggested that membrane flow between these different organelles may play a role in regulating their size. 

O'Garra lab

Gene activity database could reduce the use of research animals

Transcriptional profiling unveils type I and II interferon networks in blood and tissues across diseases

Singhania et al., Nature Communications, 10, 2887 (2019)

A research team led by group leader Anne O’Garra and co-ordinated by Christine Graham developed a comprehensive database of gene activity in mice across ten disease models. The work could significantly reduce research animal use, as rather than having to create mice, and then infect, cull, obtain samples from them and extract and sequence the RNA, researchers will be able to use the team’s app to check the activity of any gene across a range of diseases without needing to use their own mice.

The dataset and app show the activity of every mouse gene – more than 45,000 genes – in the blood of mice with ten different diseases. For the six diseases that involve the lung, samples from the lung were also examined. 

Read the full news story.

Svejstrup lab

The anti-terminator proteins

SCAF4 and SCAF8, mRNA anti-terminator proteins 

Gregersen et al., Cell, 177, 1797-1813.e18 (2019)

Research led by Jesper Svejstrup's group at the Crick identified the role of two proteins, SCAF4 and SCAF 8, finding that they are responsible for making sure that DNA is correctly copied to create messenger RNA (mRNA), without stopping before the gene is correctly expressed. When SCAF4 and SCAF8 were both lost from cells, truncated mRNA and protein products that lacked vital domains were produced, and cells were unable to survive. The two proteins work together to ensure that gene expression is correctly terminated, ensuring that mRNA is the appropriate length.

Ralser lab

Climate change has a long-term impact on a species adaptability

Ice-age climate adaptations trap the alpine marmot in a state of low genetic diversity

Gossmann et al., Current Biology, 29, 1712-1720.e7

Markus Ralser’s group found that climate change events can have a lasting effect on the genetic diversity of a species. By studying alpine marmots, a large rodent well-adapted to cold climates, the group found that the animal has some of the lowest genetic diversity of all wild mammals. By reconstructing the marmot’s genetic past, they found that it lost its genetic diversity during the last ice age through multiple adaptations to the climate.

While alpine marmots are not currently near extinction, they’re so genetically similar that they could struggle to adapt to new environmental conditions. 

Read the full news story.

Tybulewicz lab

Patterns of genes

Gene expression dysregulation domains are not a specific feature of Down syndrome

Ahlfors et al., Nature Communications, 10, 2489 (2019)

Victor Tybulewicz’s group, with James Briscoe at the Crick and collaborators at UCL, investigated gene expression dysregulation domains (GEDDs) using a mouse model of Down Syndrome. Their work disproves earlier work proposing that GEDDs, patterned segments of increased or decreased gene expression affecting all chromosomes, were a specific feature of Down Syndrome.

The team found that GEDDs were present not only in the Down Syndrome mouse models, but also wherever gene expression had changed. Their work showed that GEDDs result instead from clusters of co-regulated genes, a normal function of genome organisation.

Tate lab

Smart drug design to prevent malaria treatment resistance

Structure-guided identification of resistance breaking antimalarial N‑Myristoyltransferase inhibitors

Schlott et al., Cell Chemical Biology, 26, 991-1000.e7 (2019)

A team led by Tony Holder’s group at the Crick and Ed Tate’s group at Imperial College London, found that resistance to malaria treatments could be avoided by studying the mechanism of drug resistance during the drug development process. 

The researchers created malaria parasites resistant to a promising new type of antimalarial drugs. They could then analysis the structural changes of the drug target causing the resistance. With this knowledge they were able to identify compounds that can overcome this resistance. If the likelihood of resistance is examined in the early stages of drug development, it could reduce the risk of resistance in the years to come.

Read the news story.

Ule lab

Working together to determine cells’ fate

Cross-regulation between TDP-43 and paraspeckles promotes pluripotency-differentiation transition

Modic et al., Molecular Cell, 74, 951-965 (2019)

A paper in Molecular Cell from Jernej Ule’s group, led by research scientist Miha Modic, has described how pluripotent stem cells decide to turn into a different type of cell or remain as they are. They found that the protein TDP-43 and the long non-coding RNA Neat1 work together to determine what the cells will do next.

As both TDP-43 and Neat1 have links to the progressive neurological disease, amyotrophic lateral sclerosis (ALS), this work showing the links between them will help to develop a better understanding of the disease.

Yardimci lab

Unwinding DNA

The mechanism of DNA unwinding by the eukaryotic replicative helicase

Burnham et al., Nature Communications, 10, 2159 (2019)

Researchers Daniel Burnham, Hazal Kose, and Hasan Yardimci from the Single-Molecule Imaging of Genome Duplication and Maintenance Laboratory, and collaborator Rebecca Hoyle, discovered that the process of DNA unwinding that occurs when cells divide is more complicated and interesting than previously thought. 

CMG, an enzyme responsible for unwinding DNA during replication, was found to move in an unexpected manner. Rather than unwinding DNA unidirectionally, moving continuously forward along the length of the DNA, CMG unwinds via a more random process, ‘stuttering’ along the DNA, moving forwards and backwards as it progresses. The new understanding gives vital information about one of the most fundamental aspects of cell division.