Publication highlights

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Explore a selection of research cases studies from the past five years.

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Intro

Researchers at the Crick are tackling the big questions about human health and disease, and new findings are published every week.

Our faculty have picked some of the most significant papers published by Crick scientists, all of which are freely available thanks to our open science policy.

Highlights

Filter by year of publication

New insights into signalling enzyme in inflammatory response

A study from the Svejstrup lab has uncovered new insights into the enzyme cGAS, a key component of the innate immune system, showing that cGAS also senses dysfunctional protein production. They present an unexpected mechanism of cGAS activation by ribosome collision, which could inform our understanding of inflammatory responses to viral infection.

Translation stress and collided ribosomes are co-activators of cGAS

Published in Molecular Cell

Published

New insights into how the spinal cord develops

The Briscoe lab has used single cell mRNA sequencing to study the developing human spinal cord during gestational weeks 4 to 7. The team compared their results with the ones obtained in mice and found similarities as well as human-specific differences. This data is available as an open resource and will prove useful for future studies into sensory and motor control systems.

Single cell transcriptome profiling of the human developing spinal cord reveals a conserved genetic programme with human specific features

Published in Development

Published

New insights into protein mutation causing ALS

A new study led by postdoc Martina Hallegger and the Ule lab describes what happens when the RNA binding protein TDP-43 is mutated and its condensation properties change. The protein is often mutated in the rare neurological disease, amyotrophic lateral sclerosis (ALS).

TDP-43 condensation properties specify its RNA-binding and regulatory repertoire

Published in Cell

Published

Bone marrow backup needed to tackle respiratory infections

Researchers in the Reis e Sousa lab have found how the immune system triggers an ‘emergency’ dendritic cell response during infection. Dendritic cells have an important role in the immune system, detecting infectious bacteria, fungi or viruses that have entered the body and alerting T cells which recognise and attack the invader. However, there are few dendritic cells in healthy tissue like the lungs which means that, on infection, their numbers need to be boosted. In their study, the team monitored dendritic cells in mice infected with flu virus and found that, after infection, new dendritic cells are released from the bone marrow in response to a chemokine ‘distress’ signal which directs them to the site of infection.

Recruitment of dendritic cell progenitors to foci of influenza A virus infection sustains immunity

Published in Science Immunology

Published

CD1d-mediated lipid presentation by CD11c+ cells regulates intestinal homeostasis

Intestinal homeostasis requires a continuous dialogue between commensal bacteria and intestinal immune cells. Natural Killer T (NKT) cells are a population of CD1d-restricted lipid-reactive lymphocytes contributing to the regulation of mucosal immunity, but the mechanisms underlying this are poorly understood. Here we show that lipid presentation by CD1d+ intestinal dendritic cells and macrophages controls NKT cell function and activation which in turn regulates commensal bacteria and immune cell populations in the gut. These results reveal an NKT cell-dendritic cell crosstalk as a key mechanism for the regulation of intestinal homeostasis.

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Published in EMBO Journal

Published

Image of mouse eyeball taken with light-sheet fluorescent microscopy, with the blood vessels shown in green.

Mouse retinal cell behaviour in space and time using light sheet fluorescence microscopy

We successfully performed the first lightsheet 3D/4D imaging of mouse retinas (focussing on vessels and neurons) to demonstrate that current confocal methods distort vessel tissue. This brings a much improved way to observe and quantify the devastating changes to vessels and neurons in retinopathy mouse models.

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Published in eLife

Published

Phospho-dependent regulation of SAMHD1 oligomerisation couples catalysis and restriction

This study explained the mechanism of SAMHD1 regulation by phosphorylation/tetramerisation and correlated restriction activity with the capacity of SAMHD1 to form long lived, stable tetramers. These data form the basis of the prevailing model for SAMHD1 restriction of HIV-1 where dNTP-stabilised SAMHD1 tetramers deplete and maintain low levels of dNTPs in the non-permissive cells resistant to HIV-1 infection.

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Published in PLOS Pathogens

Published

A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells

This study showed that egress involves an enzyme cascade in which the serine protease SUB1 activates a second, cysteine protease called SERA6, enabling SERA6 to rapidly and precisely cleave the major red cell cytoskeletal protein β-spectrin and dismantle the cytoskeleton. It provides the first plausible model to explain how the parasite accomplishes timely rupture of its host cell membrane.

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Published in Nature Microbiology

Published

Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor

A study led by the Blackman lab has shed new light on a key pathway that allows the malaria parasite to escape from the host’s red blood cells. Their findings identify a target that could be used to develop a new class of antimalarial drug designed to prevent disease progression.

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Published in The EMBO Journal

Published

Reconstitution of a functional human thymus by postnatal stromal progenitor cells and natural whole-organ scaffolds

In this paper we define the heterogeneity and the clonogenic potential of human thymus stroma; characterise progenitor cells capable of extensive expansion in vitro, thereby achieving clinically relevant numbers with resilience to long-term storage; and report an epithelial-mesenchymal hybrid phenotype of thymus epithelial cells in vivo and in vitro that affects cell behaviour, a unique feature among any epithelia so far reported. We describe a protocol for organs that lack a main vascular access that allowed us to specify the role of natural ECM in supporting organ morphogenesis ex vivo and in vivo; and reconstitute a functional human thymus long-term in vivo.

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Published in Nature Communications

Published

Stabilization of reversed replication forks by telomerase drives telomere catastrophe

This study defined the mechanism leading to critically short telomeres in the absence of RTEL1 and showed that telomerase, which extends telomeres in normal cells, is pathological when forks encounter an obstacle within the telomere. We showed that replication forks stall and reverse at persistent t-loops, which creates a pseudo-telomere substrate that is inappropriately stabilised by telomerase. Removing telomerase or blocking replication fork reversal rescued telomere dysfunction in Rtel1 deficient cells. We proposed that when persistent t-loops stall the replisome, telomerase inhibits fork restart, triggering the excision of the t-loop by SLX1/4 and loss of a substantial part of the telomere.

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Published in Cell

Published

Rad51 paralogs remodel pre-synaptic Rad51 filaments to stimulate homologous recombination

This study was the first to demonstrate that RAD51 paralogues bind to and structurally remodel the pre-synaptic RAD-51-ssDNA filament to a stabilised, “open”, and flexible conformation, which facilitates strand exchange with the template duplex. We showed that RAD51 paralogues act by binding the end of the presynaptic filament, which induces a conformational change that stabilises RAD-51 bound to ssDNA and primes the filament for strand exchange. These observations established for the first time the underlying mechanism of HR stimulation by Rad51 paralogues and revealed a new paradigm for the action of HR mediator proteins.

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Published in Cell

Published

TRF2-independent chromosome end protection during pluripotency

This work revealed that telomere protection is solved by distinct mechanisms in pluripotent and somatic tissues. In somatic cells, TRF2 sequesters the telomere within a t-loop, preventing telomere end-to-end fusions and inviability. In contrast, TRF2 is dispensable for telomere protection in pluripotent cells; ESCs lacking TRF2 grow normally, do not fuse their telomeres and form functional t-loops. Upon differentiation this unique attribute of stem cells is lost and TRF2 assumes its full role in end protection. The retention of end protection in the presence of t-loops, but absence of TRF2, confirmed that t-loops are a key mediator of telomere end protection irrespectively of how they form.

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Published in Nature

Published

Microscope images of mouse and human spinal cord development at equivalent stages.

Species-specific pace of development is associated with differences in protein stability

Despite evolutionarily conservation of molecular mechanisms, the speed of development varies substantially between species. Using in vitro directed differentiation of embryonic stem cells to motor neurons, we show that the programme of motor neuron differentiation runs twice as fast in mouse as in human. We provide evidence that a two-fold increase in protein stability and cell cycle duration in human cells compared to mouse can account for the slower pace of human development, indicating that global differences in kinetic parameters play a major role in interspecies differences in developmental tempo. This study establishes a new experimental system in which to address fundamental questions.

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Published in Science

Published

Nervous system regionalization entails axial allocation before neural differentiation

The prevailing view of neural induction in vertebrate embryos had been that cells are initially induced with anterior (forebrain) identity and then caudalising signals convert a proportion to posterior fates (spinal cord). Using chromatin accessibility, to define how cells adopt region-specific neural fates, combined with genetic and biochemical perturbations, we found that contrary to the established model, cells commit to a regional identity before acquiring neural identity. These findings prompt a revision to textbook models of neural induction. The study illustrates our adoption of new genomic methods (ATACseq) to address long-standing questions, and our capacity to productively collaborate with computational biologists.

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Published in Cell

Published

Restriction of memory B cell differentiation at the germinal center B cell positive selection stage

Memory B cells (MBCs) are key for protection from reinfection. However, it is mechanistically unclear how germinal center (GC) B cells differentiate into MBCs. MYC is transiently induced in cells fated for GC expansion and plasma cell (PC) formation, so-called positively selected GC B cells. We found that these cells coexpressed MYC and MIZ1 (MYC-interacting zinc-finger protein 1 [ZBTB17]). MYC and MIZ1 are transcriptional activators; however, they form a transcriptional repressor complex that represses MIZ1 target genes. Mice lacking MYC-MIZ1 complexes displayed impaired cell cycle entry of positively selected GC B cells and reduced GC B cell expansion and PC formation. Notably, absence of MYC-MIZ1 complexes in positively selected GC B cells led to a gene expression profile alike that of MBCs and increased MBC differentiation. Thus, at the GC positive selection stage, MYC-MIZ1 complexes are required for effective GC expansion and PC formation and to restrict MBC differentiation. We propose that MYC and MIZ1 form a module that regulates GC B cell fate.

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Published in Journal of Experimental Medicine

Published

Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth

Memory B cells (MBCs) and plasma cells (PCs) are formed during the so-called germinal center (GC) B cell reaction. In the GC reaction B cells mutate their B cell receptor (BCR) genes and those that acquire a higher-affinity BCR for a pathogen antigen are presumably selected to survive and differentiate, whereas B cells carrying a lower-affinity BCR die. However, this cannot explain retention of GC B cells with varied BCR affinities and the formation of MBCs that normally carry lower-affinity BCRs. This work re-defines selection of GC B cells as permissive to ensure clonal diversity and broad protection.

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Published in Proceedings of the National Academy of Sciences of USA

Published

D-Cycloserine destruction by alanine racemase and the limit of irreversible inhibition

D-cycloserine is an antibiotic used for decades to treat drug resistant tuberculosis. Its inhibition mechanism came into question when in a previous paper we determined alanine racemase activity in “fully inhibited” cells. This study demonstrated a previously unknown path during the assumed irreversible inhibition of alanine racemase that leads to the destruction of the antibiotic, meaning that alanine racemase is not irreversibly inhibited by the drug. The paper highlights the complexity of studying the chemical mechanisms of inhibition of enzymes and points to a novel strategy to design D-cycloserine analogues with improved properties.

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Published in Nature Chemical Biology

Published

Structural basis for retroviral integration into nucleosomes

Here, we described a cryo-EM structure of a retroviral intasome in a functional complex with a nucleosome. The structure revealed a multivalent interface of the viral integration machinery and chromatin, involving both gyres of nucleosomal DNA and histones. Whilst the histone octamer remains intact, the DNA is lifted from its surface to allow for strand transfer at highly preferred integration sites. These data provided a unique snapshot of an enzyme recognizing and acting upon nucleosomal DNA. The structure was the first to illustrate nucleosome flexibility facilitating a biological process and, as such, had far-reaching implications for chromosome biology.

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Published in Nature

Published

Image depicting the structure of the active site of the integrase enzyme bound with the drug bictegravir.

Structural basis of second-generation HIV integrase inhibitor action and viral resistance

HIV integrase inhibitors represent some of the most impactful antimicrobial inhibitors. The second-generation drugs display improved barriers to the emergence of resistance, which spearheaded their worldwide rollout. Yet not even the most advanced compounds are immune to viral resistance. Our results explained the mechanism of viral resistance associated with the most common drug resistance mutations. Furthermore, we established the key difference between the first and second-generation strand transfer inhibitors, which will inform further development of this drug class.

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Published in Science

Published