Publication highlights

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.

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 and UCL have shown that genetic messages, called mRNAs, are misplaced in nerve cells in a model of Alzheimer's disease and frontotemporal dementia. They looked at corticial neurons specialised from skin cells from people with inherited forms of Alzheimer's disease or FTD who had mutations in APP or PSEN1 genes (Alzheimer's disease) and VCP (FTD). Between 82 and 140 mRNAs were found in a different place in the neurons with the mutations compared to control neurons. These included ten that were common to both diseases, all found to carry messages from genes related to mitochondrial function. The team also found that mitochondrial DNA was leaking out of the mitochondria, and that diseased neurons had fewer and smaller mitochondria. Treating these cells with a drug called ML240 returned the misplaced mRNAs to their typical locations, reduced the amount of mitochondrial DNA leakage and raised mitochondrial activity back to normal levels.

Researchers at UCL and the Francis Crick Institute have, for the first time, identified the origin of cardiac cells using 3D images of a heart forming in real-time, inside a living mouse embryo. The team used a technique called advanced light-sheet microscopy on a specially engineered mouse model, where a thin sheet of light is used to illuminate and take detailed pictures of tiny samples, creating clear 3D images without causing any damage to living tissue. They were able to track individual cells as they moved and divided over the course of two days – from a critical stage of development known as gastrulation through to the point where the primitive heart begins to take shape. This allowed the researchers to identify the cellular origins of the heart. The study’s findings could revolutionise how scientists understand and treat congenital heart defects.

The initiation of DNA replication occurs at tens of thousands of sites on the human genome during every S phase, but in the absence of any consensus DNA sequence, it is unclear how these sites are specified. Researchers at the University of Cambridge and the Crick identified sites with increased density during quiescence and G1 phase that overlap with DNA replication origins. The increased density derives from changes made by enzymes at these sites, and inhibition of these enzymes reversibly prevented DNA replication and cell proliferation. These findings provide a mechanism for the epigenetic specification and semiconservative inheritance of DNA replication origin sites, and for the once-per-cell cycle control of origin activation.

When we think about cell signalling, be it developmental transitions, or be it the sequential events that make up the cell growth and division cycle, we think of regulators. Typically, a kinase is thought to exert control over downstream events, such as the cyclin-dependent kinase (CDK), which has master control over cell cycle progression. Researchers at the Crick revisit how CDK phosphorylates each of its many cell cycle targets at the right time. Not merely a decision by the kinase, they realise that the substrates themselves contribute to deciding when their phosphorylation time has come. ‘Substrate control’ likely more widely forms part of cell signalling decisions.

Researchers have shown that the transfer of genes from bacteria into more complex organisms can give them an advantage but requires remodelling of the host’s biology. The lab explored the integration of a horizontally transferred gene coding for an enzyme called squalene-hopene cyclase (Shc1) from bacteria into S. japonicus yeast. They found that S. japonicus switches between using an enzyme that generates sterols in the presence of oxygen, Erg1, and the horizontally acquired Shc1 enzyme to produce hopanoids in conditions without oxygen. They showed that hopanoids are best accommodated in the membrane if it is made of asymmetrical lipids, so S. japonicus has adapted to produce two different lengths of fatty acids. The researchers concluded that the bacterial gene provided S. japonicus with an advantage against other yeast species, especially in high temperature and low oxygen environments.

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.