Mapping mouse airways, brown fat and exercise, and cancerous dependencies.
By Broad Communications
Credit: Erik Jacobs
Welcome to the August 3, 2018 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Single-cell mapping of the airway
In a comprehensive single-cell analysis of airway cells in mice, validated in human tissue, a team led by Daniel Montoro, Adam Haber, Moshe Biton, Broad core institute member and Klarman Cell Observatory director Aviv Regev, and Broad associate member Jayaraj Rajagopal reveals molecular details critical to understanding lung disease. The team identified a rare cell type in airway tissue, previously uncharacterized in the scientific literature, that appears to play a key role in the biology of cystic fibrosis. The molecular survey also characterized gene expression patterns and cellular development for other new cell subtypes, with broad implications for all diseases of the airway. Check out the study in Nature and learn more in the Broad news story, along with news coverage in STAT, Scientific American, Science News, and The Scientist.
Muscle function impacts exercise, right off the BAT
Exercise is known to increase secretion of small proteins called myokines in skeletal muscles, thus leading to the development of brown adipose tissue (BAT). However, whether BAT affects muscle function was not known. In a study published in Cell Metabolism, a research team led by institute member Evan Rosen, highlights that the loss of transcription factor IRF4 in BAT reduces exercise capacity and induces expression of myostatin, a protein known to inhibit muscle function, in mouse models. They also observed that overexpression of IRF4 reduces myostatin expression and increases exercise capacity. Their findings suggest that BAT affects skeletal muscle function, driven by IRF4 and myostatin.
A case of molecular piracy in cancer
The BAF complex, an assemblage of proteins that together act as a chromatin remodeler, opens tightly packed DNA so that transcriptional machinery and other factors can access genes for transcription. In Molecular Cell, Gabriel Sandoval, John Pulice, institute member William Hahn, and institute member and Epigenomics Program co-director Cigall Kadoch (all also at the Dana-Farber Cancer Institute) and colleagues reveal that a cancerous fusion protein called TMPRSS2-ERG redirects BAF complexes to sites in the genome that in normal prostate cells they would not otherwise target, turning on tumor-promoting gene programs. Read more in a Broad news story.
To kill these cells, you need p53 as well
Most Ewing sarcoma tumors express non-mutated (i.e., “wild-type”) p53 tumor suppressor proteins. A team led by associate member Loren Walensky in the Broad’s Chemical Biology and Therapeutic Sciences Program, and institute member Kimberly Stegmaier and Bjorn Stolte of the Broad’s Cancer Program performed a genome-scale CRISPR-Cas9 screening study and found four proteins that Ewing sarcoma cells depend upon and that can be targeted with drugs. Reporting in the Journal of Experimental Medicine, the researchers also found inhibitors of those proteins that kill tumor cells, and that intact p53 was required for the inhibitors’ anti-tumor effects.