Publication highlights

Go inside our research

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

Maternal pluripotency factors initiate extensive chromatin remodelling to predefine first response to inductive signals

This paper, and another published the same year (Gentsch GE et al. (2019) iScience, 16, 485-498), analysed gene activation in the early Xenopus embryo and asked what causes cells to become competent to respond to Wnt, Nodal and BMP signalling. We identified regulatory DNA sequences associated with early-expressed genes, and deduced from them that the maternal pluripotency factors Pou5f3 and Sox3 remodel compacted chromatin before the onset of inductive signalling. This remodelling includes the opening and marking of thousands of regulatory elements, extensive chromatin looping, and the co-recruitment of signal-mediating transcription factors. Our work informs our understanding of how pluripotent stem cells interpret inductive signals.

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Published in Nature Communications

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

SCAF4 and SCAF8, mRNA anti-terminator proteins

SCAF4 and SCAF8 were isolated in the mid-90s as proteins that bind the RNAPII C-terminal repeat domain (CTD) but little or nothing was known about their cellular function. This paper describes their function as the first eukaryotic mRNA anti-terminator proteins. Together, SCAF4 and SCAF8 coordinate the transition between elongation and termination, ensuring correct polyA site selection and RNAPII transcriptional termination in human cells.

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Published in Cell

Published

Neoantigen-directed immune escape in lung cancer evolution

We analysed the first 100 TRACERx patients to unravel how escape from adaptive immunity occurs in non-small cell lung cancer. Immune ‘hot’ tumours, characterised by a brisk lymphoid infiltrate, had been selected for HLA LOH or deleterious mutations in the antigen presentation machinery. In contrast immune ‘cold’ tumours with an absent lymphoid infiltrate had lost clonal neoantigens through DNA copy number loss events. We found evidence for negative selection of subclones early in tumour evolution harbouring neoantigens in genes essential for non-small cell lung cancer viability. Patient outcome was worse for tumours with evidence of an immune evasion event.

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Published in Nature

Published

ATG9A shapes the forming autophagosome through Arfaptin 2 and phosphatidylinositol 4-kinase IIIβ

This paper represents an important step forward in our understanding of ATG9, the only multi-spanning autophagy protein and a major focus of my lab’s current work. Here we discovered the composition of the ATG9 vesicle and uncovered an important role for a protein which can induce membrane curvature and a lipid kinase. I chose this work as it has provided us with important insights into the function of ATG9A.

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Published in Journal of Cell Biology

Published

Molecular determinants regulating selective binding of autophagy adapters and receptors to ATG8 proteins

This paper follows on from our work on WAC and the role of centrosomes in autophagy. We discovered an important centriolar protein has a specific motif (LIR motif) enabling its binding to a key autophagy protein. In collaborative work, we determined the structure and the important features of the LIR motif, and extended the findings to a group of autophagy proteins to provide an important advance on our understanding of selective autophagy. I chose this work because it is a tour de force of structure and biochemistry and a very substantial collaboration between Structural Biology and Peptide Chemistry STPs

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Published in Nature Communications

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

RPEL-family rhoGAPs link Rac/Cdc42 GTP loading to G-actin availability

This paper shows that the ArhGAP9/12/15/27 and ArhGAP32/33 families of rhoGAPs are RPEL proteins whose activity is coupled to G-actin concentration. G-actin forms a 1:1 complex with these ArhGAPs, interacting with an RPEL motif located between the PH and GAP domains, thereby inhibiting their GAP activity. Mutations that block G-actin binding exhibit elevated GAP activity towards their substrate GTPases Rac and Cdc42. Strikingly, treatment of cells with drugs enhancing or inhibiting G-actin/ArhGAP interaction has corresponding effects on Rac GTP loading. These results establish a novel homeostatic feedback loop, in which ArhGAP12-family (and presumably ArhGAP32-family) GAP activity increases when G-actin levels become limiting.

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Published in Nature Cell Biology

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

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

DNA entry into and exit out of the cohesin ring by an interlocking gate mechanism

Building on our successful biochemical reconstitution of topological cohesin loading onto DNA, we completed the reconstitution of both dynamic loading as well as unloading. We realised that both loading and unloading follow a very similar trajectory through sequential ATPase and kleisin gates, only one of which can be open at any one time. This formed the basis for our unified DNA passage proposal both into and out of the ring.

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Published in Cell

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

Cell clustering promotes a metabolic switch that supports metastatic colonization

We show that the clustering of cancer cells following detachment from ECM results in hypoxia, which activates mitophagy to remove damaged mitochondria and reductive metabolism to support glycolysis. These responses limit mitochondrial ROS production, allowing cell survival and metastasis.

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Published in Cell Metabolism

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

Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis

Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. This is the first vaccine against tuberculosis to be shown effective in humans since the advent of BCG in 1921. A product development and further testing plan has recently been agreed and we will contribute to the latter.

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Published in New England Journal of Medicine

Published