RESCUEing RNAs, exploiting bacterial appetites, delving into a cancer dependency map, and more.
Research Roundup: July 12, 2019
Welcome to the July 12, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
A new RNA editor to the RESCUE
In Science, a team led by Omar Abudayyeh, Jonathan Gootenberg, and core institute member Feng Zhang reports a new CRISPR-based RNA editor that can convert cytosine bases into uridine. The platform, called RESCUE (RNA Editing for Specific C to U Exchange), significantly expands the landscape that CRISPR tools can target, and enables easier targeting of sites that regulate the activity and function of many proteins. The work builds on REPAIR, an RNA-editing tool the team developed in 2017 to convert adenine bases into inosine. Read more in an MIT/Broad news story.
Hashing out a method to tag one nucleus at a time
Single-nucleus RNA-sequencing (snRNA-seq) is a key method used to investigate cell states, types, and functions in complex tissues. Thus snRNA-seq helps in the advancement of genetics studies, clinical trials and building cellular atlases. However, in order to maximize the success of snRNA-seq, there is an urgent need to eliminate batch effects associated with handling a large number of samples and reduce associated costs. A team led by Jellert Gaublomme, Bo Li, institute scientist Orit Rozenblatt-Rosen, core institute member and Klarman Cell Observatory director Aviv Regev, and colleagues addressed these limitations by developing an approach called “nucleus hashing” in which they labeled the nucleus of individual cells with unique DNA-tagged antibodies. Read more in Nature Communications.
Transcription factor could indicate likelihood of pancreatic cancer relapse
About half of patients with pancreatic neuroendocrine tumors (PNETs) that do not produce excess hormones, called non-functional PNETs, relapse with metastatic disease. In Nature Medicine, researchers suggest a possible way to predict the likelihood of relapse for individual patients. Yotam Drier, Chuck Epstein, Noam Shoresh, Elizabeth Gaskell, and institute member and Epigenomics Program director Bradley Bernstein found that 84 percent of analyzed non-functional PNETs expressed one or both of two transcription factors. Patients with tumors expressing the factor PDX1, alone or with the other factor, were very unlikely to experience a relapse compared to those not expressing it. This information could ultimately help doctors determine how closely to monitor a patient post-surgery.
Bacteria’s appetite may be key to their demise
Ramping up bacteria’s metabolic rate could increase the effectiveness of antibiotics because these medicines target processes that demand energy. In essence, bacteria need to consume their poison for it to kill them, and the more they consume, the more likely their death. In Cell Metabolism, Jonathan Stokes, Allison Lopatkin, and institute member James Collins — all in the Broad's Infectious Disease and Microbiome Program — present current knowledge on the relationship between bacterial metabolism and antibiotic efficacy. The researchers discuss our understanding of this relationship towards the development of highly potent and precise antibacterial therapies that could overcome mechanisms bacteria use to evade antibiotics.
NuRDing out over sickle cell disease
Turning fetal hemoglobin genes back on could treat sickle cell disease. A team led by associate member Daniel Bauer and including Falak Sher, Mir Hossain, and Davide Seruggia of Boston Children's Hospital used pooled CRISPR dense mutagenesis to disrupt members of the nucleosome remodeling and deacetylase (NuRD) chromatin complex, which controls fetal hemoglobin levels. Appearing in Nature Genetics, the work discovered regions within NuRD, such as its tether to the CHD4 nucleosome remodeler, that could be promising targets to therapeutically boost fetal hemoglobin while avoiding cellular toxicity. The study illustrates how agnostic gene editing can identify protein sequences with specific biological roles within ubiquitous chromatin complexes.
Children of older fathers are more likely to have psychiatric and developmental disorders, an effect previously attributed to new mutations that accumulate in paternal germ cells as men age. A team led by Jacob Taylor and institute member Elise Robinson in the Stanley Center for Psychiatric Research analyzed whole-exome sequencing data from parent-child trios and found that paternal-age-related mutations confer a slightly increased risk for autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability, and schizophrenia (SCZ). Described in Nature Communications, the work also found that the paternal-age-related risk for ASD and SCZ can’t be fully explained by new mutations, so other factors are also at play.
The dependency map of cancer takes shape
Throughout its nearly 15-year history, the Cancer Dependency Map (DepMap) project has been cataloging hundreds of cancer cell lines' genetic vulnerabilities and small molecule sensitivities, all with the goal of bringing about new treatment options for patients. In a feature story on the Broadminded blog, DepMap leaders Todd Golub, William Hahn, Jesse Boehm, Aviad Tsherniak, and Francisca Vazquez dive into the project's origins, efforts, and impacts to date, and the collaborative blend of functional genetics, chemical biology, and data science that makes it unique.