Publication highlights

A subset of dendritic cells, type 1 conventional dendritic cells (cDC1s), plays a key role in recognising material from dead or damaged cells and showing fragments of that material to killer T cells in a process known as cross-presentation. This is critical for defence against some viruses and cancer. This study uncovers how one cDC1 receptor, DNGR-1, promotes cross-presentation of antigens from dead cells while keeping the cell otherwise 'quiet'. The team discovered that this behaviour depends on a single amino acid within the receptor. Changing this amino acid switches DNGR-1 into an activating receptor, but at the cost of losing cross-presentation efficiency. The findings reveal that DNGR-1 has evolved to prioritise information gathering from dead cells over full immune activation, helping the body learn from self-damage without triggering harmful inflammation.

Histone modifications are chemical marks that help regulate DNA functions. One of the most common, H4K16 acetylation (H4K16ac), is known for turning genes on in fruit flies, and it has been assumed to do so in mammalian cells too. Researchers at the Crick and the European Institute of Oncology found that in human cells, H4K16ac does not control gene activity but instead organises when and where DNA is copied during cell division. Without it, regions of the genome enriched for repetitive elements (LTRs) replicate prematurely, globally disrupting the temporal control of DNA replication. Their findings reveal an unexpected role for histone acetylation in safeguarding genome replication accuracy.

Researchers at the Crick have shown that early in infection with Mycobacterium tuberculosis, the bacterium that causes TB, molecules called type I IFNs trigger neutrophil swarming in the lung. This impedes interactions between protective immune cells called macrophages and T cells required for early control of infection. They found that neutrophil swarming is reversed by blockade of the type I IFN receptor, allowing interaction of these protective immune cells to control TB disease.

In this study, researchers at the Crick and UCL investigated how an epigenetic change called DNA methylation cooperates with genetic changes in non-small cell lung cancer (NSCLC) using 217 tumour and normal regions from 59 TRACERx patients. This is the first multiregional lung cancer cohort integrating genomic, transcriptomic, and epigenomic data to map tumour evolution in such detail. They uncovered a novel mechanism, where DNA methylation fine-tunes how oncogenes are switched on together by compacting the DNA. We also identified hypermethylated driver genes emerging early in tumour evolution and developed a new metric, Mr/Mn, to distinguish functional from passenger methylation changes. Our work highlights epigenetic drivers with therapeutic potential.

Several models of cell fate lineages have been presented, some proposing a traditional straight path and others a more dynamic model, where cell fate remains more flexible. Researchers at the Crick combined a range of experimental techniques - single cell transcriptomics, quantitative live cell imaging and mathematical modelling - to track cell fate and determine which path is the right one. They found that there was no singular path, and these theories were not competing explanations but complementary snapshots of human development. The team also observed the influence of two important signalling molecules, Activin and BMP4, in determining which route cells would take between mesoderm or endoderm layers.

Cells need to be made in the right place at the right time in developing tissue, but how these two cues are coordinated to control cell identify is not well understood. Using mouse stem cell models of the neural tube, researchers at the Crick found a surprising "master clock" mechanism that modifies the chromatin of neural cells, making different DNA regions accessible at specific times during development. Working with the High Throughput Screening team, they identified key molecular regulators, including a transcription factor called Nr6a1, that control the temporal programme by altering chromatin accessibility. Disrupting these factors altered the identity of cells before and after becoming specialised. The ability of temporal factors in the mice to control chromatin accessibility over time explains how the same spatial progenitor domains can produce different cell types as development progresses. Taking into account the cell’s temporal clock could help engineer the generation of specific neurons and glial cells from stem cells for regenerative medicine purposes.

In a joint effort from the Francis Crick Institute, UCL and the Netherlands Cancer Institute, researchers have demonstrated that lung cancers consist of different subclones that differ intrinsically in their capacity to evade immune attack. Cancers are genetically heterogeneous – consisting of different subclones – but to what extent this affects immune evasion remained largely unclear. Now, using samples from the TRACERx cancer evolution study, the team have established organoids – mini-tumours growing in 3D - from different regions from the same tumour, and further separated these into individual subclones. Challenging these with immune cells from the patient’s tumour showed that different subclones isolated from the same tumour differ profoundly in their ability to trigger an immune response. This provides direct functional evidence that subclonal cancer evolution has important consequences for the ability to evade immune attack.

Researchers at the Crick and UCL Queen Square Institute of Neurology have shown that alpha-synuclein, the protein that aggregates in Parkinson’s disease, can trigger widespread RNA editing in astrocytes as part of an anti-viral innate immune response. They used human stem cells to generate astrocytes, the most abundant cell type in the brain. Using molecular biology, genomic and computational approaches, they showed that forms of alpha-synuclein trigger the same innate immune pathways in astrocytes that viruses do. One consequence of this response was a marked increase in RNA editing, with extensive changes throughout the genetic code as it is converted into proteins.