Improving prion disease survival, deeper understanding of cancer mutations, getting to the core of polygenic traits, and more.
Research Roundup: August 9, 2019
Welcome to the August 9, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
The CD40 protein helps activate certain immune cells, but cells keep the protein's levels under tight control so that they can fight off pathogens without triggering autoimmunity. Chang Jiang (BWH/HMS), associate member Benjamin Gewurz, institute scientist and Genetic Perturbation Platform associate director John Doench, and others performed a CRISPR/Cas9 screen in a human B cell line to identify proteins that regulate CD40 responses. Appearing in Cell Reports, their work showed that the tumor suppressor FBXO11 and the RNA binding protein CELF1 support CD40 expression, while WTAP, ESCRT, and DUSP10 all suppress it. The results provide a resource for future studies and highlight potential drug targets for cancer and autoimmune disease.
Improving prion disease survival
Prion disease is a deadly disorder with no cure or treatments, and is caused by a misfolded, toxic form of the prion protein that leads to neurodegeneration. Associated scientists Sonia Vallabh and Eric Vallabh Minikel at the Stanley Center for Psychiatric Research and collaborators injected into prion-infected mice antisense oligonucleotides (ASOs) that decrease levels of the prion protein mRNA. Publishing in JCI Insight, the researchers reported that treatments given every two to three months prolonged survival times by 61 to 98 percent. Even a single injection 120 days after infection, when symptoms started to appear, extended survival 55 percent. The team concludes that ASOs slow the disease by lowering prion protein levels, and that ASOs are a promising treatment for neurodegeneration. Read more in this NIH News Release.
Revealing the cause of Leigh syndrome’s neurological symptoms
Excess oxygen in the brain likely causes the symptoms of Leigh syndrome, the most common pediatric mitochondrial disease, based on experiments in a mouse model. Co-director of the Broad Metabolism Program and institute member Vamsi Mootha and collaborators showed that inducing severe anemia in Leigh syndrome mice or treating them with carbon monoxide, which both reduce oxygen levels, reversed neurological disease. However, genetically activating the hypoxia transcriptional response was not beneficial. While the treatments that were effective are not feasible for humans, understanding the cause of Leigh syndrome’s symptoms lays a foundation for future therapy development. Read the full study in Cell Metabolism.
Making sense of mutations in cancer
TP53, which encodes for the tumor suppressor protein p53, is the most frequently mutated gene in human cancer. However, the precise mechanisms underlying the specific mutations have not been determined conclusively. About 80 percent of mutations in TP53 are protein-altering missense mutations. A team led by institute member Benjamin Ebert, postdoctoral scholar Steffen Boettcher of the Broad Cancer Program, and colleagues used CRISPR-Cas9 to introduce a series of missense mutations in human leukemia cell lines to uncover specific mechanisms. The team found that these mutations led to loss of function and dominant-negative effects, rather than gain of function activity as has been postulated commonly in the past. Read more in Science.
Putting the pause on transcription
Histone deacetylase proteins are often described as gene-expression inhibitors that compact chromatin, making the DNA inaccessible in areas where transcription could otherwise begin. To better understand the detailed mechanisms in this process, a team led by Broad Summer Scholars Program and Research Science Institute alum Catherine Li (Mass General Hospital), visiting scientist Alon Goren (University of California, San Diego), associate member Raul Mostoslavsky of the Cancer Program, and colleagues investigated the action of the histone deacetylase SIRT6. They now describe SIRT6's role as a key regulator of transcription and its interactions with RNA polymerase II and related proteins. Learn more in Molecular Cell.
Getting to the core of polygenic traits
Thousands of genetic variants influence heritability of complex traits and common diseases. Associate member Alkes Price of the Program in Medical and Population Genetics, Luke O’Connor, and others hypothesized that those variants don’t contribute equally, but that few loci influence the trait much more than the rest. Reporting in the American Journal of Human Genetics, they developed a method to describe how evenly a trait’s heritability is spread across the genome and used it to analyze 33 common traits. Their results suggest that for most complex traits, a limited number of genes have critical effects when mutated, and the work offers insight to prioritize GWAS loci for follow-up studies.
Mono microbe modifies mitochondrial metabolism
Epstein-Barr virus (EBV), which causes infectious mononucleosis, is also causally associated with some B cell lymphomas. A team led by associate member Ben Gewurz of the Genetic Perturbation Platform, Michael Weekes (University of Cambridge), Liang Wei Wang (HMS/BWH), Luis Nobre (Cambridge) and Ina Ersing (BWH), in collaboration with postdoctoral scholar Hongying Shen and institute member Vamsi Mootha of the Broad Metabolism Program, studied how EBV remodels the metabolism of B cells to drive cancer. They found that EBV infection hijacks the B cell mitochondria and the one-carbon (1C) folate metabolism pathway to support cancer cell growth. Appearing in Cell Metabolism, the work suggests that targeting the 1C pathway could help treat B lymphomas.