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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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

The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes

Aneuploidy is remarkably common in human embryos, and most often results from defective recombination in the maternal germ line. There is therefore great interest in determining mechanisms that eliminate recombination-defective oocytes, and how defects in these mechanisms cause chromosome abnormalities in offspring. In this study, we showed that recombination-defective oocytes are eliminated via the BCL-2 pathway components Puma, Noxa and Bax. Our findings raised the possibility that allelic variants of the BCL-2 pathway could influence the risk of embryonic aneuploidy.

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Published in Nature Communications

Published

A single-cell transcriptome atlas of marsupial embryogenesis and X inactivation

Single-cell RNA sequencing of embryos can resolve the transcriptional landscape of development at unprecedented resolution, but such studies of mammalian embryos had focused exclusively on placental species. Analysis of mammalian outgroups might identify deeply-conserved lineage specification and pluripotency factors. In this study, we performed the first single-cell RNA-sequencing in a marsupial, which diverged from eutherians 160 million years ago. We identified many critical developmental regulators pre-dating the placental-marsupial separation which are thus likely to be especially important for embryogenesis. Our study has important implications for understanding the high rates of miscarriage in humans and for developing improved conditions for assisted reproduction.

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Published in Nature

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

A structure-based mechanism for DNA entry into the cohesin ring

Cohesin is a ring-shaped protein complex that topologically entraps DNA to fulfil key functions in chromosome architecture. In a collaborative and multidisciplinary approach, we used cryo-EM, biochemical and biophysical techniques to describe how ATP-fuelled structural changes of the cohesin complex drive the DNA entry reaction into the cohesin ring. This solves one of the outstanding riddles in molecular biology.

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Published in Molecular 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

YAP1/TAZ drives ependymoma-like tumour formation in mice

We showed that active YAP1 in radial glia derived neural precursor cells induces ependymoma-like tumours in mice. We demonstrated that YAP1 is necessary and sufficient using mouse models. We found that transcription coactivator HOPX, a factor consistently suppressed in malignancies, is highly expressed in our mouse models and in YAP1-fusion human ependymoma. HOPX differentiates YAP1-fusion subtype from the highly malignant RELA-fusion human ependymomas. This supports the notion for subtype-specific care for ependymoma.

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Published in Nature Communications

Published

Credit Alex Cagan. Cartoon of Peter Van Loo.

The evolutionary history of 2,658 cancers

This study leverages molecular archaeology of cancer approaches in a large-scale pan-cancer setting to construct timelines of tumour evolution, showing when in a tumour’s evolutionary history key events typically happen. It demonstrates that tumours typically develop over multiple years to sometimes decades, highlighting opportunities for early detection.

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Published in Nature

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

Glypicans shield the Wnt lipid moiety to enable signalling at a distance

This paper solves the Wnt solubility problem, which has preoccupied the Wnt field for the past 15 years. It explains how the lipid of Wnts can be maintained in the extracellular space.

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Published in Nature

Published

Patterning and growth control in vivo by an engineered GFP gradient

By merging the power of molecular genetics, basic physical chemistry and mathematical modeling we show quantitatively how an inert protein, GFP, can be turned into a morphogen that provides positional information in a developing tissue, the Drosophila wing disc. This is the first time that an active synthetic morphogen gradient has been reconstituted in vivo. Because the properties of the synthetic gradient can be experimentally modulated, a physical analysis of molecular determinants of morphogen gradients becomes possible.

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Published in Science

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

Tissue sections of mouse lungs, after infection with influenza. The image on the left is the control and the image on the right is from mice without receptors for interferon lambda. The lungs where interferon lambda signalling is blocked (right) shows improved epithelial cell growth and differentiation (in red).

Type I and III interferons disrupt lung epithelial repair during recovery from viral infection

We showed that interferons (IFNs), known to have antiviral effect, can aggravate respiratory viral infection if present late during infection when epithelial repair sets in. IFN-β and, most potently, IFN-λ reduce airway epithelial proliferation and differentiation in that recovery phase. This is important to understand the complex roles of IFNs in viral infections and has important implications for IFN treatments as presently discussed for COVID-19.

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Published in Science

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