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.

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.

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.

Fanconi Anemia is a devastating genetic disease characterised by genome instability, developmental defects, and cancer predisposition, involving defects in the FA DNA repair pathway. Central to the FA pathway is the FANCM protein, which acts as both a DNA damage sensor to modify another protein called FANCD2, and as a fascinating motor protein that “zips up” DNA. This report is the first comprehensive structural and mechanistic understanding of how FANCM recognises DNA damage and activates modification of the FANCD2 and FANCI proteins through a process called monoubiquitination. The paper reveals how FANCM evolved from being a DNA repair motor protein into a complex sensor coupling DNA damage recognition to selective pathway activation.

Researchers at the Crick and NPL, as part of the CRUK Grand Challenges team Rosetta, have developed a multimodal imaging pipeline that extends upon the principles of correlative light, electron, and ion microscopy (CLEIM), which combines confocal microscopy reporter or probe-based fluorescence, electron microscopy (EM), stable isotope labelling and Nanoscale secondary ion mass spectrometry (NanoSIMS). Their protocol allows an unprecedented extraction of biological information from specimens, whilst being based on a series of well-established and widely available technologies, thus allowing quick adaptation of the protocol for individual research needs. This integration provides a multifaceted view of the tissue microenvironment, capturing both the internal cellular architecture and the intricate metabolic dynamics occurring within. The researchers tested their pipeline by imaging the incorporation of carbon from glucose into B and T cells in mouse liver tumours.

Loss of the tumour suppressor gene CDKN2A is a common early event in development of the pre-cancerous condition Barrett's oesophagus. Around 1% of Barrett's patients go on to develop oesophageal adenocarcinoma, but rather than enhancing this progression, as would be expected, early CDKN2A loss is actually protective. Having made this striking observation, the team at the Crick and collaborators showed that the reason lies with a second tumour suppressor gene, TP53. Loss of TP53 is a key driver of transformation into oesophageal cancer, but if CDKN2A is also missing, the Barrett's cells are too weakened to progress. CDKN2A changes sides to become a villain later in the process: if it's lost after the cancer has developed, it promotes a more aggressive tumour.

Researchers at the Crick and the UCL Cancer Institute have identified a genetic change which happens early in lung cancer development, that makes cancer cells divide abnormally and become harder to treat. They studied non-small cell lung cancer samples from the Cancer Research UK-funded TRACERx study, to investigate which genetic changes make two hallmarks of cancer, chromosomal instability and whole genome doubling, more likely. They identified that a gene called FAT1 was mutated in lung cancer cells with unstable chromosomes before they doubled their genomes. Cells with a complete loss of FAT1 couldn’t divide properly to produce two new cells. When FAT1 and another gene involved in cell size regulation called YAP1 were removed, the cancer cells no longer doubled their genomes. This suggests that drugs that block YAP1 could be particularly effective against cells with high levels of chromosomal instability.

In this work, Jones and colleagues shed light on the role of a highly conserved yet poorly understood gene, FAM83F. This gene has been linked with human cancer, yet very little is known about its function. Using zebrafish embryonic development as a model, they show that loss of FAM83F leads to impairment of the mechanism by which cells clear away and degrade cellular materials. Mutant zebrafish embryos are more sensitive to stress caused by DNA damage and hatch prematurely. These findings have implications for our understanding of the role of FAM83F in both development and disease.

Wear-and-tear means the lining of the gut is continually refurbished. Gut stem cells self-renew or differentiate (change state) into transit amplifying (TA) cells, which in turn either cycle or differentiate into mature gut epithelial cells. TA cells have an additional superpower: they can de-differentiate to replenish the stem cell pool after damage. Vivian Li's lab have found that when ARID3A is knocked out in mice, there are more mature cells and fewer TA cells, as the balance between the two states is disturbed. Further, the ability to repair irradiation-induced damage to the stem cell pool is hampered as damaged stem cells cannot be replaced efficiently from the depleted TA cell pool. These findings reveal the hitherto unrecognised role of ARID3A in coordinating the gut proliferation–differentiation ratio important for both steady-state and injury-induced gut regeneration.