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

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Active sampling state dynamically enhances olfactory bulb odor representation

Animals engage actively with their environment, yet how active sampling strategies impact neural activity was unknown. We showed that mice adapt sniffing during learning in a way that enhances neuronal representation. Furthermore, this work resolves a long-standing conundrum that seemingly non-olfactory information is prominently represented in the OB: context influences sniffing, which in turn changes neural activity.

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Published in Neuron

Published

Microscopic image of a mouse colon.

The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity

This paper demonstrates a cell intrinsic role for AHR in intestinal stem cells. AHR deficiency in intestinal epithelium causes dysregulation of the Wnt pathway, overproliferation of crypt stem cells and impaired epithelial differentiation following injury, culminating in tumorigenesis.

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Published in Immunity

Published

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

We investigated how intratumour heterogeneity affects response to checkpoint blockade and how cancers might be treated based on evolutionary principles. Durable clinical benefit to checkpoint blockade in lung cancer and melanoma was associated with a high burden of clonal neoantigens; in contrast, tumours that progressed early on therapy had a higher burden of heterogeneous neoantigens. We could predict clonal neoantigens present in every tumour cell and identify immune cells that recognise them, suggesting that development of adoptive T cell or vaccination strategies targeting such clonal neoantigens might limit therapeutic escape and resistance mechanisms.

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Published in Science

Published

Germinal center B cells recognize antigen through a specialized immune synapse architecture

Using new high-throughput imaging designed for rare cell subsets, we revealed that germinal centre B cells form uniquely patterned immune synapses to bind antigens. The separation of antigen into small clusters, along with specific cytoskeletal organisation results in enhanced mechanical forces transferred onto the B cell receptor-antigen bonds, increasing the mechanical affinity-discrimination power of germinal centre B cells compared to other B cell subsets. The work implicated germinal centre B cell mechanics in selection of high-affinity B cell clones in antibody responses and introduced novel DNA nanosensors for measuring cellular forces.

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Published in Nature Immunology

Published

Mutual dependence of the MRTF-SRF and YAP-TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics

The MRTF-SRF and the YAP-TEAD transcriptional regulatory networks both respond to extracellular signals and mechanical stimuli: the MRTFs are controlled directly by G-actin, while YAP activity is somehow potentiated by F-actin. Cancer-associated fibroblasts play an important pro-invasive role in stimulating cancer progression, and previous studies have shown that this involves YAP-TEAD signalling. This paper shows that CAFs also exhibit mechanically-dependent MRTF activation, which is also required for their contractile and pro-invasive activity. The two pathways are mutually dependent, requiring recruitment of MRTF and YAP to DNA via their respective DNA-binding partners, and reflecting their ability to control cytoskeletal gene expression.

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Published in Genes & Development

Published

Tracking cancer evolution reveals constrained routes to metastases: TRACERx Renal

This is the first prospective study in any cancer type that resolved the origin of the metastasising clone in the primary tumour characterising its genetic features and uncovering high risk events that confer risk of death.

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Published in Cell

Published

Deterministic evolutionary trajectories influence primary tumor growth: TRACERx Renal

This is the largest genomic study ever to be conducted in renal cell cancer and the first to show how evolutionary features of the tumour impact the clinical phenotype. Patent arising.

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Published in Cell

Published

WNK1 kinase balances T cell adhesion versus migration in vivo

In this study we identified the WNK1 kinase as a negative regulator of CD4+ T cell adhesion and a positive regulator of T cell migration. Furthermore, we showed that WNK1 controls migration through the OXSR1 and STK39 kinases and the SLC12A2 ion co-transporter. This was an unexpected finding since WNK1 had been previously shown to regulate salt homeostasis in the kidney. Our study is the first to have implicated movement of Na+, K+ and Cl- ions in the regulation of T cell migration.

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Published in Nature Immunology

Published

Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration

In this study we showed that the Dp1Tyb mouse model of DS has locomotor defects, mapped the causative genes to a 25-gene region and identified that Dyrk1a is one of these. Furthermore, we found an unexpected progressive loss of motor neurons in these mice and showed that a similar loss is seen in humans with DS.

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Published in PLOS Genetics

Published

Heteromeric RNP assembly at LINEs controls lineage-specific RNA processing

One of the major surprises of our iCLIP studies was the major role that transposable elements play as hubs for RNP assembly. Here, we uncover multiple roles of LINEs in RNP assembly, and show how this helps to create repressive environment in introns, while also driving the evolution of new tissue-specific exons.

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Published in Cell

Published

Repression of divergent noncoding transcription by a sequence-specific transcription factor

Transcription factors typically activate transcription by recruiting cofactors, but our data in this paper illustrate a new function. We show that the sequence-specific transcription factor Rap1 prevents regulatory elements from initiating transcription in the divergent direction. We define a novel mechanism for providing directionality towards productive transcription, as Rap1 promotes directionality, at least in part, by directly interfering with transcription initiation in the divergent direction. Our study reveals a new important layer of regulation, describing how genomes restrict the accumulation of aberrant transcripts and ensure productive coding gene expression.

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Published in Molecular Cell

Published

A role for p53 in the adaptation to glutamine starvation through the expression of SLC1A3

In this paper we show that the ability of cells to survive glutamine depletion depends on aspartate metabolism, which is supported by the aspartate/glutamate transporter SLC1A3. The tumor suppressor p53 is shown to induce the expression of SLC1A3, explaining in part how p53 can help cancer cells survive under glutamine starvation.

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Published in Cell Metabolism

Published

Isoform diversity in the Arp2/3 complex determines actin filament dynamics

The Arp2/3 complex, consisting of seven evolutionarily conserved subunits, generates branched actin networks during many fundamental cellular processes. Taking advantage of actin based motility of Vaccinia virus as a model system, we demonstrate for the first time that in humans the Arp2/3 complex is actually a family of different complexes with distinct actin-nucleating properties.

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Published in Nature Cell Biology

Published

Unresolved recombination intermediates lead to ultra-fine anaphase bridges, chromosome breaks and aberrations

The generation of CRISPR-Cas9 GEN1 k/o cell lines (supplemented with MUS81 siRNA) allowed us to develop the first model system to analyse the phenotypes of ‘resolvase-deficient’ human cells. We discovered that recombination intermediates persist until anaphase (despite the presence of the BLM-TopoIII-RMI1-RMI2 dissolvasome) where they form ultra-fine bridges (UFBs). These UFBs represent a new class of ultrafine bridges (we termed them HR-UFBs) distinct from replication stress induced UFBs or centromeric UFBs. HR-UFBs were targeted and processed by PICH/BLM, leading to the formation of ssDNA bridges that were broken at cytokinesis. Loss of GEN1 and MUS81 activity led to synthetic lethality.

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Published in Nature Cell Biology

Published

Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[18F]fluoro-ᴅ-glucose positron emission and computed tomography

This work used high-resolution PET/CT imaging to establish for the first time in humans the existence of a high-risk asymptomatic transition state between latent infection and active disease. The technique is thus a phenotypic benchmark for further experimental medicine studies of interventions to prevent progression of asymptomatic subclinical tuberculosis.

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Published in Nature Medicine

Published