Diamond Annual Review 2023/24

23 D I A M O N D L I G H T S O U R C E A N N U A L R E V I E W 2 0 2 3 / 2 4 A closer look at how cells package DNA Our cells use an ensemble of histone proteins to fold and package the DNA genome into the nucleus. A complex of histone proteins act as a spool around which 147 base pairs of DNA can wind like thread. Multiple histone spools called nucleosomes can be found along the length of a DNA molecule and coil its strands into so-called chromatin. Beyond efficiently folding DNA to fit inside the nucleus, histones play vital roles in regulating gene expression, DNA replication, and repair by loosening or tightening their grip on DNA and controlling its exposure to enzymes. Scientists at the University of Oxford collaborated with the electron Bio- Imaging Centre (eBIC) at Diamond Light Source to capture chromatin in the nucleus of immune T cells. They used Cryo-electron tomography (cryoET) to image cells in a state that resembles physiological conditions. The researchers observed that chromatin was more flexible and heterogenous in shape than the models suggested. This was the first study to demonstrate that cryoET of thin lamellae could be used to observe chromatin organisation under physiologically relevant conditions. Next, the researchers aim to use this technique to study the structure of chromatin at the ends of chromosomes called telomeres, which shorten with age. They would also like to explore how the structure of chromatin changes in different diseases like cancer and how this affects processes like gene expression or the integration of virus DNA into the genome. Hou, Z. et al. DOI: 10.1038/s41467-023-42072-1 Figure: Averaged structures of nucleosomes with or without histone 1 (H1). Image taken from Hou et al. Nat Commun (2023) under a CC BY 4.0 license. A first peek at a “crass” virus The human gut is brimming with bacteria that aid with digestion and support immune health. In turn, bacteria-infecting viruses called bacteriophages keep these bacterial populations in check, preventing any one bacterial species from outgrowing the rest. Crassviruses are the most common variety of bacteriophages, accounting for nearly 95% of gut viruses in some healthy people. Despite their wide prevalence, scientists knew very little about them and had not determined their structure. In early crassvirus research, scientists studied viral genomes from multiple different faecal samples in a process called “cross assembly” from which the name “crass” is derived. Initial research into this novel group of viruses has largely been restricted to studying their genes as a result. Now they have for the first time observed what these microbes look like under the microscope in granular detail. In collaboration with eBIC, they used cryo-electron microscopy (cryoEM) to solve the structure of ΦcrAss001, the first crassvirus ever isolated from human faecal samples. Researchers reconstructed the virus’ anatomy to a near-atomic resolution of 3.1 Ångströms (Å). Despite crassviruses sharing very few of their DNA sequences with other known bacteriophages, Bayfield noted that they adopted similar, conserved structures. ΦcrAss001 possesses an icosahedral head and a tail, like other viruses, such as the famous moon-lander shaped T4 bacteriophage that infects E. coli . These anatomical parts serve crucial functions for the virus: the head stows away viral DNA in neatly folded piles while the tail threads the DNA out of the head and into a bacterial host. The head mostly contained neatly and tightly packed DNA without much free space. However, the team spotted a hollow region near the base of the head where DNA was sparse and in disarray. They hypothesised that viral proteins might occupy the seemingly vacant space. ΦcrAss001 is just one of a multitude of crassviruses. In future work, they aim to solve the structure of different viral species, including close and distant relatives, so they can triangulate what it means to be “crass” in the viral world. Bayfield, O.W. et al . DOI: 10.1038/s41586-023-06019-2 Figure: The first structure of a crassvirus showing the exterior (left) and interior (right). Like other bacteriophages, this virus contains a “head” that stashes away DNA in neat folds and a “tail” that shunts its genome into a bacterium. Image credit: Oliver Bayfield.