Research Roundup: August 24, 2018

Welcome to the August 24, 2018 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Scoping sinuses with single-cell sequencing

Chronic rhinosinusitis (CRS) is a severe nasal allergy that sometimes leads to the development of nasal polyps, arising from epithelial cells that line the respiratory tract. In a study published in Nature, Jose Ordovas-Montanes, Broad associate member Alex K. Shalek, and collaborators used single-cell RNA sequencing to study gene expression changes in 36,740 individual cells lining the nasal cavity in both healthy individuals and those across the disease spectrum of CRS. They present the first cellular map of a human barrier tissue during inflammation and provide insights into why chronic inflammatory disorders are often so difficult to treat. Learn more in a Brigham and Women’s Hospital press release and an MIT news story.

Discovery value of whole-genome sequencing

Plasma lipids, including total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, are heritable risk factors for cardiovascular disease. A team led by associate member Pradeep Natarajan, Seyedeh Maryam Zekavat, institute member and Cardiovascular Disease Initiative co-director Sekar Kathiresan, and colleagues tested the value of large-scale whole genome sequencing to identify variants associated with these risk factors. The researchers analyzed genomes from 16,324 people and uncovered new associations between plasma lipids and common genetic variants, and highlighted the need for improved methods to study rare noncoding variants. The team also applied whole-genome sequencing to develop a polygenic risk score for LDL cholesterol. Read the full story in Nature Communications.

PACE takes on soluble protein expression

Engineering proteins for improved or novel functions often leads to a reduction in their solubility as well, impeding their development and use. To address this problem, a team led by Tina Wang and core institute member and Merkin Institute for Transformative Technologies director David Liu developed a new phage-assisted continuous protein evolution system that allows the user to simultaneously — and independently — select for both soluble expression and another trait of interest. The team describes the new system, called SE-PACE, and reports a series of applications for it in this week’s Nature Chemical Biology. Their data establish SE-PACE as a rapid method to improve the expression, and in some cases the stability, of a variety of proteins while preserving their function.

Leveraging human proteins as antibiotic candidates

Antibiotic-resistant infections lead to nearly 23,000 deaths per year in the US, and new treatment options are essential. Antimicrobial peptides (AMPs), released by most living organisms as the first line of defense against infections, are one potential alternative to antibiotics. In a study published in ACS Synthetic Biology, Broad associate member Timothy Lu in the Cell Circuits Program, Cesar de la Fuente-Nunez (MIT), Eugenio Notomista (University of Naples), and collaborators used computationally-guided data mining approaches to search 2,000 human proteins and discovered 800 novel AMPs as candidates for antibiotics. Learn more in this MIT news story.

Tracing a childhood neuroblastoma’s genetic dependencies

Institute member Kimberly Stegmaier of the Broad Cancer Program, Adam Durbin, and Neekesh Dharia, with colleagues from the Whitehead Institute and Dana-Farber Cancer Institute, led an effort to unearth tumor-specific gene dependencies in a type of childhood neuroblastoma driven by amplification of the MYCN gene. Using CRISPR-Cas9 screens in cancer cell lines, the team identified 147 genes linked to the growth of MYCN-amplified neuroblastoma. In follow-up experiments, the team found that a subset of these genes — transcription factors that form the transcriptional core regulatory circuitry (CRC) — are essential for survival of the MYCN-amplified tumors. Read their work in Nature Genetics.

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