The keys to cancer drug resistance, building better germline cells, and finding flu's vulnerabilities.
By Broad Communications
Credit: Erik Jacobs
Welcome to the January 10, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
The kinase keymaster
Mutated cells that are resistant to kinase-inhibiting cancer drugs can help reveal whether the drugs are hitting their intended molecular targets, but it’s been difficult to predict the best genomic spots to alter. A team including Nicole Persky and Desiree Hernandez of the Genetic Perturbation Platform and Cory Johannessen, Lisa Brenan, and Mariana Do Carmo of the Cancer Program used saturation mutagenesis to reveal nearly 30 residues in kinase genes that can mediate resistance. A number of these sites appear to induce resistance across different kinases, and a single site, dubbed the Keymaster, appears to drive resistance via kinase activation. Taking the same approach for other protein families could help improve drug discovery. Read more in Nature Structural and Molecular Biology.
The genesis of germ cells
The process of making germline cells from human pluripotent stem cells is called in vitro gametogenesis. The success of this process depends on the quality of a subset of cells called primordial germ cells (PGCs). A team led by Di Chen (UCLA), postdoctoral scholars Na Sun and Lei Hou, associate member Manolis Kellis of the Epigenomics Program, and Amander Clark (UCLA) performed single-cell RNA sequencing of more than 100,000 human PGC-like cells and used computational algorithms to understand the molecular events that lead to the development of these cells. Their work, published in Cell Reports, uncovered an essential mechanism associated with successful initiation of in vitro gametogenesis.
A new view of the flu
The influenza A virus (IAV) poses a major public health threat. Like most viruses, IAV has a relatively small genome of its own, and relies on its host’s machinery to replicate. Using CRISPR-Cas9 screens to systematically disable genes in human cells, a team led by Bo Li of the Harvard University Virology Program, institute member and Cell Circuits Program co-director Nir Hacohen, and colleagues has identified 121 host genes required for IAV to complete its life cycle — some of which could inform new therapeutic targets. The team further reports on associated mechanistic discoveries and a new analytical approach that incorporates their findings into the existing evidence base for influenza dependencies. Read more in Nature Communications.