Publication highlights

Organs such as the intestine, liver and pancreas are spatially specialised, but how and why this differs between sexes is poorly understood. Researchers in the Organ Development and Physiology Laboratory used the fruit fly intestine to investigate the basis of these sex-specific differences. Using whole-organ 3D mapping and metabolic profiling, they found clear sex- and region-specific patterns of gene activity and metabolism. They showed these patterns are controlled by the opposing effects of the sex-determining factor Doublesex and the growth regulator Myc. In males, Doublesex suppresses Myc, leading to higher Myc activity in females. Female Myc increases cell DNA content, changes lipid-processing genes, and promotes fat storage in specific gut regions, supporting whole-body fat reserves and reproduction.

Researchers in the Stem Cell Biology and Developmental Genetics Laboratory at the Crick and IIS BioGipuzkoa have uncovered a role for the Sox2 regulatory region 2 (Srr2), a small non-coding DNA enhancer, in governing neural stem cell fate decisions in the adult mouse. They found that Srr2 maintains the levels of the key stem cell factor SOX2 during neural stem cell proliferation. Loss of Srr2 leads to widespread chromatin compaction, impaired activation of neurogenic gene programs, and defects in neuronal and oligodendroglial differentiation. Importantly, the enhancer-dependent regulation of SOX2 is required not only for gene expression but also for establishing a chromatin landscape that keeps neural stem cells competent to respond to differentiation cues. These findings provide new mechanistic insight into how regulatory elements shape stem cell behaviour and brain plasticity.

During development, cells must maintain a stable identity while also responding to signals that drive changes required for development. For example, a cell must maintain a stable sense of direction - its polarity - to preserve order in the developing embryo and ensure cells are oriented correctly to generate functional tissues. Yet cells also must be adaptable to signals that arise during development to drive cell rearrangements. Using the embryo of a small worm (C. elegans) as a model, researchers in the Polarity and Patterning Networks Laboratory found that cells resolve this conflict through oscillations linked to their cell division cycle. These oscillations tune the sensitivity of cells such that, shortly after a cell is born, there is a brief window in which they are sensitive to cues and thus can align their polarity with local signals. Once this window closes, polarity is locked in. If this process is disrupted, cells ignore signals critical for coordinating polarity with development, leading to defects in cell positioning and fate specification.

Proteins transit into and out of the cell nucleus through tightly regulated gateways known as nuclear pore complexes. Researchers in the Single Molecule Mechanobiology Laboratory have showed that a protein’s local structural properties—specifically how stable or flexible different regions are—significantly affect how efficiently it is transported. Proteins move more rapidly through the pore if disordered, less mechanically stable regions enter first. This principle holds across diverse protein types and is supported by experimental and computational approaches. Notably, many human transcription factors position their nuclear targeting signals in these flexible regions, suggesting that protein orientation provides an additional mechanism for regulating nuclear transport efficiency.

This study from the Crick and the University of Oxford examines how small genetic changes in a non-coding gene, RNU4-2, contribute to neurodevelopmental disorders, including ReNU syndrome. By systematically testing every possible variant in the gene, the researchers identified which changes disrupt normal cellular function and how severely. Their approach outperformed existing computational predictions and clarified which variants are disease-causing, including those previously uncertain. The work also uncovered a distinct recessive disorder linked to different regions of the same gene, as detailed in an accompanying clinical study published in Nature Genetics. Overall, the findings provide a comprehensive map of function across RNU4-2, offering important advances for diagnosis, prognosis, and the development of targeted therapies.

Purifying valuable medicines is often slow and wasteful because many compounds in a mixture are chemically similar and can require harsh separation steps. In this work, researchers at the Crick demonstrate a reusable 'molecular container' that can selectively capture a chosen drug molecule from a complex mixture and then release it on demand under mild conditions. The key advance is a self-assembled palladium-based cage that can be switched between two stable forms simply by changing the counter-ions. Each form presents a different binding pocket, enabling a programmable catch-and-release cycle: one state extracts the target, and the other releases it cleanly for collection. As a proof of concept, the approach isolates the antiviral drug darunavir from a mixture of multiple drugs with high recovery and excellent purity, while leaving negligible residual metal that readily meets pharmaceutical safety limits.

Researchers at the Crick have developed a highly sensitive tool called transient transcriptome combined with transcription start site sequencing (TT-TSS-seq), that accurately maps the exact 'start site' where RNA polymerases begin reading DNA, known as transcription. By refining the enzymatic steps to capture start sites, they show that many genes actually have multiple starting points, even if they only produce one final product. This new approach provides a high-resolution map of gene activity, helping scientists better understand how cells regulate gene expression.