Publication highlights

Researchers at the Crick and UCL have shown that reported that astrocytes show signs of hypoxic stress long before neurons begin to die in ALS. Using stem cells from patients to generate astrocytes carrying ALS-linked mutations in a gene called VCP, which is linked to inherited forms of ALS, the team showed that astrocytes exhibited clear signs of 'pseudo-hypoxia'. This meant they had switched on a low-oxygen response despite being in normal oxygen conditions. This was driven by HIF-1a, a master regulator of how cells respond to oxygen. Instead of being degraded under normal conditions, it had accumulated in the nucleus and activated genes involved in metabolism, energy production and stress responses. As a result ALS astrocytes showed mitochondrial dysfunction and a reduced ability to support motor neurons. This is particularly exhibited as an inability to correct the mislocalisation of RNA-binding proteins, a well-known molecular hallmark of ALS, compromising neuron survival.

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.

Human induced pluripotent stem cells (iPSCs) mimic early embryos and can become any cell type, making them a powerful tool to study development and disease. However, most existing cell lines aren't suited to study sex differences. In collaboration with AstraZeneca, Turner lab researchers Ruta Meleckyte and Wazeer Varsally addressed this by creating new iPSCs with either XX (female) or XY (male) sex chromosomes. All other chromosomes were identical, so any differences observed can be linked to sex. These openly available iPSCs will enable more accurate modelling of sex-specific biology and may help in developing better, more personalised treatments in the future.

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.

Researchers at the Crick have developed a CRISPR-based screening method to rapidly assess how the loss of individual Cryptosporidium genes influence parasite survival in vivo. Using this method, they examined the parasite’s pyrimidine salvage pathway and a set of leading Cryptosporidium vaccine candidates. This targeted screening method is highly versatile and will enable researchers to more rapidly expand the knowledge base for Cryptosporidium infection biology.

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.