Publication highlights

Mitochondria are the cell’s powerhouses and are essential for organismal health. When they malfunction, proteins meant to enter them can accumulate outside and act as distress signals, alerting the cell to potential damage. Researchers at the University of British Columbia, in collaboration with colleagues at the Crick, discovered that a small region of a mitochondrial protein plays a key role in activating a protective program that promotes mitochondrial recovery. Under normal conditions, this region enables the protein to enter mitochondria, but when blocked, it switches roles to signal stress. This finding reveals a natural “canary in a coal mine” for mitochondrial dysfunction and opens new possibilities for treating neurodegenerative and other mitochondria-related diseases.

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.

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.

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 the Francis Crick Institute have revealed insight into why embryos erase a key epigenetic mark during early development, suggesting this may have evolved to help form a placenta. The team at the Crick investigated, for the first time, epigenetic changes in embryos of a marsupial, which diverged from eutherian mammals 160 million years ago. They created a map of DNA methylation in opossum eggs, sperm and embryos, finding that levels of methylation in eggs and sperm were more similar to each other than they were in eutherians. However, unlike eutherians, opossum embryos did not undergo a full wiping event. Instead, DNA methylation was retained in the early embryo, with loss occurring much later, and DNA demethylation was largely restricted to a specific supportive tissue called the trophectoderm, which becomes the marsupial placenta. These findings show that demethylation isn’t universally required for formation of an early mammalian embryo, instead, based on their findings, the team believe that wiping may have evolved specifically for the development of the placenta.

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.

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.

Researchers have found that the small intestine grows in response to pregnancy in mice. This partially irreversible change may help mice support a pregnancy and prepare for a second. They found that pregnant mice had a longer small intestine from just seven days into the pregnancy. By the end of the pregnancy, around day 18, the small intestine was 18% longer, and it remained longer up to 35 days after lactation. The villi and crypts inside the small intestine also became longer and deeper at the same time, but returned to pre-pregnancy values just seven days after weaning. The researchers identified an increase in a membrane protein called SGLT3a early in pregnancy. This sodium and proton sensor was responsible for about 45% of the villi growth triggered by reproduction but wasn't necessary for entire small intestine lengthening. The team believe hormones may play a role in switching on the gene for SGLT3a.