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Nature Papers Present 3D Maps of Single-Cell DNA Organization, Structure of Conserved SARS-CoV-2 Element, More

Aiming to address the technical challenges of measuring three-dimensional genome organization at the single-cell level, a group of California Institute of Technology researchers has developed a method to generate high-resolution, genome-wide maps of 3D DNA organization in thousands of individual cells. The approach — called single-cell split-pool recognition of interactions by tag extension, or scSPRITE — uses split-and-pool barcoding to tag DNA fragments in the same nucleus and their 3D spatial arrangement. As scSPRITE measures multiway DNA contacts, it generates higher-resolution maps within an individual cell than can be achieved by proximity ligation, the scientists write in this week's Nature Biotechnology. Importantly, scSPRITE does not require special equipment, techniques, or training and provides increased resolution from a lower number of sequencing reads across a larger number of cells. "We expect that it will expand the availability of single-cell genome structure measurements to any molecular biology laboratory," the team writes. "Additionally, we expect that scSPRITE can be scaled to work with as few as hundreds or as many as several thousands of cells simultaneously."

A high-resolution three-dimensional cryo-electron structure of the highly conserved frameshift stimulation element (FSE) of the SARS-CoV-2 genome is presented in Nature Structural & Molecular Biology, providing new details about a potential therapeutic target for the virus. FSE is required for the balanced expression of viral proteins and has become a promising SARS-CoV-2 RNA target but remains poorly characterized. In the study, a group led by Stanford University investigators generate a 3D structure of an 88-nucleotide SARS-CoV-2 FSE RNA at 6.9-angstrom resolution by single-particle cryo-electron microscopy, which they validate through an RNA nanostructure tagging method. They find that the tertiary structure presents a topologically complex fold in which the 5' end is threaded through a ring formed inside a three-stem pseudoknot and use this structure to develop antisense oligonucleotides (ASO) that disrupt FSE function in frameshifting assays and knockdown SARS-CoV-2 virus replication in culture. "These results demonstrate the therapeutic potential of targeting the SARS-CoV-2 frameshift stimulation element, establish ASO leads for preclinical testing, and provide a structural and functional framework for further development of both ASO and small molecule compounds," the authors write.

A multivariate genome-wide association analysis of overall variation in dietary intake in thousands of individuals of European ancestry reveals new insights into the biological mechanisms that influence this behavior. As reported in this week's Nature Human Behavior, a Massachusetts General Hospital-led team performed the analysis of overall variation in dietary intake in 282,271 participants from the UK Biobank and identify 26 distinct genomic loci. Dietary intake signals map exclusively to specific brain regions and are enriched for genes expressed in specialized subtypes of certain neurons. The researchers also identify two main clusters of genetic variants for overall variation in dietary intake that were differently associated with obesity and coronary artery disease. "Our findings provide insights into the biological mechanisms that influence dietary intake, highlighting the relevance of brain-expressed genes, brain cell types, and neural processes," the study's authors write. "Furthermore, we showed that genetic variants associated with overall variation in dietary intake converge into two main groups of genetic variants that are differently associated with obesity among relatively healthy individuals of European ancestry."