Putting lung cancer proteomics and genomics together, how chromatin-changing complexes know where to go, an arms race between cells and bacteria, and more
By Broad Communications
Credit: Broad Communications
Welcome to the August 6, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
A new angle on lung cancer biology
Patients with lung squamous cell carcinoma (LSCC) have yet to benefit from the kinds of treatment advances seen with other kinds of lung cancer. The Broad Proteomics Platform's Shankha Satpathy, Karsten Krug, Pierre Jean-Beltran, DR Mani, Steven Carr, and Michael Gillette joined with collaborators in the NCI's Clinical Proteomics Tumor Analysis Consortium (CPTAC) to generate a proteogenomic picture of LSCC, one that brings genomic, transcriptomic, and proteomic data together into one comprehensive view. Writing in Cell, they identify potential new drug targets, immune regulation pathways that might help the cancer evade immunotherapies, and a new molecular subtype of LSCC. Learn more in a Broad/CPTAC news story.
PRMT’s substrate interface, uncovered and inhibited
The essential enzyme PRMT5, a therapeutic target in MTAP-deleted tumors, requires partners known as substrate adaptors for its regulatory activity. Reporting in Molecular Cell, Kathleen Mulvaney, Brian McMillan, Alessandra Ianari, core institute member William Sellers in the Cancer Program, and others identify an evolutionarily conserved peptide sequence shared among its known substrate adaptors that is necessary and sufficient for PRMT5 interaction and methylation of substrates. Growth of MTAP-deleted tumor cells is impaired by genetic disruption of the PRMT5-adaptor interface, making it a potentially druggable site. In the Journal of Medicinal Chemistry, David McKinney, Sellers, Ianari, and others in the Cancer Program and the Center for the Development of Therapeutics describe a screen for compounds that inhibit substrate adaptor binding, including the discovery of the first inhibitor of the PRMT5-substrate adaptor interface.
Cues that control chromatin changes
SWI/SNF (or BAF) complexes are a group of proteins that modulate DNA architecture and expression, and are frequently mutated in disease. However, the factors that influence when and where they bind to nucleosomes and remodel chromatin remain unknown. In Science, Nazar Mashtalir, Hai Dao (Princeton), Tom Muir (Princeton), institute member Cigall Kadoch of the Epigenomics Program, and colleagues report binding and remodeling experiments that illustrate how changes to nucleosome structure — such as histone modifications, variants, and mutations — alter the targeting and activities of SWI/SNF complexes. They show that the complexes respond to diverse signals and combinations of signals, revealing interactions that could be targets for future therapies.
Mammalian cells use a process called xenophagy to eliminate intracellular pathogens. In response, bacteria have evolved strategies to evade xenophagy and other host cell processes for survival. Now core institute member Ramnik Xavier, postdoctoral scholar Kai Liu, senior research scientist Kim Carey at the Infectious Disease and Microbiome Program, and colleagues have revealed ways in which host cells and bacteria counter-regulate lipid membrane dynamics during xenophagy to modulate an innate defense. For instance, using small interfering RNA (siRNA) against lipid kinases and phosphatases, the researchers identified SAC1, a transmembrane lipid phosphatase enzyme, as a key regulator of xenophagy. This and other findings are described in Cell Reports.
New method to study mRNA modification in single cells
Chemical modification of mRNA can affect many cellular processes, but current methods to study mRNA modification can’t be used on small samples or in single cells. Kyung Lock Kim, institute member Bradley Bernstein of the Epigenomics Program, and colleagues developed a new microscopy-based approach to quantify epigenetically modified mRNA molecules in single cells and relate these findings to cellular phenotypes. They used nanoscale technology to compare cell surface markers, gene expression, total numbers of individual mRNA transcripts, and adenosine mRNA methylation (m6A) levels, all in the same cells. Read more in Cell Reports Methods.