Research Roundup: July 17, 2020

Pooled screening in human cells and molecular understanding of Huntington’s disease and pediatric brain cancers. 

Erik Jacobs
Credit: Erik Jacobs

Welcome to the July 17, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Expanding the toolkit for genetic screens

Cas9 is the enzyme used in most genetic screening experiments, but its properties have made it difficult to employ for multiplexed, pooled screening. A team led by Peter DeWeirdt, Kendall Sanson, Annabel Sangree, Mudra Hegde, and institute scientist John Doench of the Genetic Perturbation Platform now describes a set of experimental and computational tools to enable the effective use of Cas12a from Acidaminococcus bacteria (AsCas12a) for pooled screening in human cells. The researchers developed and optimized AsCas12a for large-scale genetic screens and, in proof-of-principle experiments, revealed both known synthetic lethal interactions and a previously uncharacterized interaction between MARCH5 and WSB2 — two genes implicated in protein degradation. Learn more in Nature Biotechnology.

Transcriptomic view of Huntington’s disease

The mechanisms by which mutant huntingtin gene mHTT kills neurons in Huntington disease (HD) is not fully understood. Writing in Neuron, Hyeseung Lee, core institute member Myriam Heiman, and colleagues report on gene expression changes in striatal neurons (the cell type most vulnerable to HD) in HD patients and mouse models. They observed a release of mitochondrial RNAs that triggered activation of neuronal innate immune signaling. Their findings provide a framework for understanding the basis of mHTT toxicity and may help point to new therapeutic targets in HD. 

A brain tumor reveals its weak points

Ependymomas are a family of pediatric brain cancers with nine well-defined molecular subgroups, but that knowledge has not translated into effective treatments for the most aggressive of these tumors. By characterizing tumors from several ependymoma patients using single-cell RNA sequencing, Bernhard Englinger, Li Jiang, associate member Mariella Filbin of the Program in Medical and Population Genetics, and colleagues identified expression signatures that could better help stratify high- and low-risk patients. Their data, reported in Cancer Cell, also exposed vulnerabilities that doctors might be able to target with existing drugs.