Seeing more of the synapse, how genetics could impact diabetes screening, an exploratory epigenomic editor, and more.
Research Roundup: September 27, 2019
Welcome to the September 27, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
A tool for editing the epigenome
The insulator protein CTCF helps define “topologically associated domains” (TADs) in the genome, but studying its role in defining TAD boundaries has been difficult. Daniel Tarjan, William Flavahan, and institute member and Epigenomics Program director Bradley Bernstein devised a strategy to edit the epigenome and perturb CTCF insulators. Reporting in Nature Communications, they show that fusions of dCas9 to transcriptional repressors and DNA methyltransferases can disrupt CTCF binding to specific insulators. They use their strategies to simulate the loss of insulator proteins seen in some brain tumors, and offer a model for stably modifying genome organization and gene activity without altering DNA sequence.
Metabolic adaptations and biomarkers of clinical benefit from cancer immunotherapy
Cancer immunotherapies that inhibit the PD1 protein work for only a minority of patients. Haoxin Li, Kevin Bullock, Shuba Gopal, associate members Eliezer Van Allen, Toni Choueiri, and Marios Giannakis; institute scientist Clary Clish, institute members William Sellers and Levi Garraway, and core institute member Stuart Schreiber — representing the Cancer and Chemical Biology and Therapeutics Science programs and the Metabolomics Platform — and colleagues profiled serum metabolites in patients with advanced melanoma and kidney cancer treated with nivolumab, an anti-PD1 antibody, looking for metabolomic signatures correlating with overall patient survival. They found that increased circulating kynurenine (the product of IDO/TDO and tryptophan catabolism) was associated with an immune-suppressive tumor microenvironment. They also showed that an increase in kynurenine/tryptophan ratio is associated with worse patient survival. They also suggested that changes in serum kynurenine/tryptophan levels could be a marker for patient stratification in clinical trials testing certain immunotherapies. Read more in Nature Communications.
Using ancestry-genomic data to improve diabetes-screening
Genetic variants may influence how accurately hemoglobin A1c (HbA1c) reflects blood-glucose levels in people with diabetes. Analyzing 10,338 individuals representing several ancestries (Europeans, African-Americans, Hispanics, and East Asians) from the TOPMed program, researchers led by Chloé Sarnowski (Boston University), Aaron Leong, associate member James Meigs, and Alisa Manning of the Diabetes Research Group and collaborators were able to better characterize two genetic regions in which variants, only present in African-Americans and Hispanics, lowered HbA1c. The study demonstrated that genetic information should be considered when using HbA1c for diabetes screening so as to reduce under-diagnosis in high-risk minority groups. Read more in American Journal of Human Genetics.
Imaging a dozen synaptic proteins at once
In Nature Communications, Li Li, Karen Perez de Arce, Jeff Cottrell, and associate member Mark Bathe in the Stanley Center for Psychiatric Research and colleagues describe PRISM, a fluorescence imaging method that can rapidly image up to 12 proteins in synapses simultaneously in neuron cultures containing thousands of synapses. They started with a method that involves labelling proteins or other molecules with DNA-conjugated antibody probes, and then introducing fluorescent oligonucleotides that bind to the probes. The team then developed methods to rapidly exchange different probes to recognize different antibodies targeting different proteins. This new method allowed them to analyze a larger number of proteins in individual cells and synapses than typical methods. The team is now using this technique to study how synapses are affected by genes linked to psychiatric disorders. Read more on the Broad website.