Coronavirus doorways, Epstein-Barr hideaways, family history takeaways, and more
Research Roundup: April 24, 2020
Welcome to the April 24, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Identifying cells targeted by SARS-CoV-2
To uncover the factors that regulate ACE2, the SARS-CoV-2 entry receptor, institute member Alex Shalek, associate member José Ordovas-Montañes, Carly Ziegler, Samuel Allon, Sarah Nyquist, researchers from the Human Cell Atlas Lung Biological Network, and other collaborators investigated large single-cell RNA-sequencing datasets from human, primate, and mouse tissues. Reporting in Cell, they found that the gene encoding ACE2 is interferon-stimulated in human upper airway epithelial cells, but not in mice, raising key implications for disease models and pre-clinical therapeutic development. The researchers say the study highlights the power of the global scientific community to rapidly tackle new challenges through open sharing of data and ideas. They have made their data available via the Single Cell Portal (SCP). Learn more in an MIT news story, coverage in The Boston Globe, and a video Q&A with SCP’s Vicky Li Horst and Timothy Tickle.
How might coronavirus get in? Follow your nose
Working as part of the Human Cell Atlas Lung Biological Network, associated scientist Roby Bhattacharya, associate members José Ordovas-Montañes and Jay Rajagopal, institute members Shalek and Christine Seidman, and core institute members Deborah Hung, Aviv Regev, and Ramnik Xavier joined an international effort led by researchers at the Wellcome Sanger Institute to identify potential entry points for SARS-CoV-2. Using single-cell RNA sequencing data from many tissues and organs, the researchers found that two cell types in the nose — goblet cells and ciliated cells — express high levels of ACE2 and and another key entry protein, TMPRSS2, as do cells in the eye and intestines. Learn more in Nature Medicine and in a Sanger press release.
Standard case-control genome-wide association studies (GWAS) ignore participants’ family histories of disease. Associate member Alkes Price in the Program in Medical and Population Genetics and graduate student Margaux Hujoel in the Stanley Center for Psychiatric Research developed a new association method known as LT-FH, which takes both case-control status and family history into account. Described in Nature Genetics, the method attributes higher genetic liability to cases and controls with family history of disease, compared to those without. They used the method to analyze 12 diseases from the UK Biobank and found that it was more powerful in finding independent genome-wide-significant loci than standard GWAS methods.
The iron is hot
The recently described iron-dependent mechanism of cell death known as ferroptosis has been implicated in degenerative diseases and is a targetable vulnerability in several cancers. In a Cell Chemical Biology perspective, core institute member Stuart Schreiber and postdoctoral associate Yilong Zou in the Chemical Biology and Therapeutics Science Program describe new insights into the lipid peroxidation state that drives ferroptosis and its role in disease contexts. They also discuss gaps in the understanding of ferroptosis and key challenges that have thus far limited the full potential of targeting ferroptosis for improving human health.
The secret to a virus’s hideout
Epstein-Barr virus causes several types of cancer, but hides from the immune system in a latent form in memory B cells. To learn how the virus remains latent, Rui Guo, Chang Jiang, John Doench, associate director of the Genetic Perturbation Platform, associate member Benjamin Gewurz (Brigham and Women’s Hospital), and colleagues did a genome-wide CRISPR-Cas9 screen in Burkitt lymphoma B cells. They found various host factors, all linked to the transcription factor MYC, that repress virus reactivation. Depleting MYC or factors important for MYC expression reactivated the virus, including in Burkitt xenografts. MYC blocks reactivation by binding a specific location along the virus’s genome that’s important for viral replication. The study, published in Molecular Cell, suggests possible drug targets to maintain Burkitt latency.