Research Roundup: July 26, 2019

Welcome to the July 26, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Illuminating why a form of brain cancer is hard to kill

Glioblastoma’s resistance to treatment may stem from the plasticity of its cells, suggests a new study in Cell. Researchers led by Cyril Neftel, Mariella Filbin, and institute member Mario Suvà, together with institute member and Epigenomics Program director Bradley Bernstein and core institute member and Klarman Cell Observatory director Aviv Regev, performed single-cell RNA sequencing on over 24,000 glioblastoma cells and analyzed models of the brain cancer in the lab. They identified four glioblastoma cellular states and found genetic alterations associated with each of them. They also showed that glioblastoma cells can flip between states by expressing different sets of genes. Understanding this shape-shifting ability could support the development of better therapies. Learn more in a Broad news story.

A cellular picture of childhood brain tumor 

Medulloblastoma is a malignant childhood brain tumor with four distinct molecular subgroups. Even though the genomic characteristics of these subgroups are well defined, a complete picture of their cellular origins was not fully known. Using single-cell RNA sequencing, a research team led by Volker Hovestadt, Filbin, Bernstein, Suvà, and collaborators in St. Jude Children’s Research Hospital, provide a detailed analysis and molecular picture of medulloblastoma’s cellular and developmental states. The findings will inform future therapeutic approaches. Learn more in Nature and a St. Jude’s news story. 

The building blocks of ulcerative colitis

The underlying mechanisms of ulcerative colitis — a chronic, painful inflammatory bowel disease — are complex and not well understood. In Cell, a team led by Christopher Smillie, Moshe Biton, José Ordovas-Montañes, Ashwin Ananthakrishnan (MGH), institute member Alex Shalek, core institute member and Infectious Disease and Microbiome Program co-director Ramnik Xavier, and Aviv Regev now describes a high-resolution atlas of the colon, generated by studying 366,650 individual cells from healthy individuals and patients with ulcerative colitis. The data, part of the international Human Cell Atlas project, offer new insights into how the tissue is remodeled in disease and open the doors to many diagnostic and therapeutic hypotheses. Read more in a Broad news story.

Freeing up a molecular traffic jam

We have long known that dozens of inherited diseases called toxic proteinopathies are caused by the build-up of specific misfolded proteins in cells. Where and how they accumulate, however, has remained a mystery. In studying MUC1 kidney disease (a rare kidney disorder), Moran Dvela-Levitt, institute member and Kidney Disease Initiative director Anna Greka, and colleagues in the Broad's Center for the Development of Therapeutics have found that some of these toxic proteinopathies may share a single, previously unrecognized cellular mechanism: a jam at a specific step in the secretory pathway involving a cargo receptor called TMED9. They report in Cell that a chemical compound called BRD4780 can break the jam and restore cells to normal functioning, providing an excellent starting point for therapeutic development. Read more in a Broad news story.

A disease’s defensive diversity

Immune mechanisms underlying lupus nephritis (LN), a complication of systemic lupus erythematosus (SLE), are unclear, and treatment is ineffective and often toxic. A team led by institute member and Cell Circuits Program co-driector Nir Hacohen, Betty Diamond (Feinstein Institute), Arnon Arazi, Deepak Rao (BWH), Celine Berthier (University of Michigan), and others in the Accelerating Medicines Partnership in SLE network performed single-cell RNA sequencing of kidney samples from patients with LN and healthy controls. They discovered 21 subsets of white blood cells active in LN inflammation. Appearing in Nature Immunology, the work suggests urine could one day replace kidney biopsies.

The time of my life

Interventions such as drugs or diet can extend the lifespan of mammals, but it’s unclear how. A team led by associate member Vadim Gladyshev and Alexander Tyshkovskiy (BWH/HMS), with help from institute scientist and Metabolomics Platform senior director Clary Clish, analyzed 17 such interventions in mice and found that certain patterns of gene expression are associated with longevity, regardless of the intervention type. They used the “longevity signatures,” including upregulation of oxidative phosphorylation and drug metabolism, to help identify drugs that might extend lifespan, findings that could one day help delay the effects of aging in humans. Read more in Cell Metabolism. 

Evolving base editors for greater efficiency

Base editors enable precise conversion of DNA base pairs in living cells. Cytosine base editors (CBEs) convert target C•G base pairs into T•A base pairs and can be highly efficient in cells that express them robustly, but can perform poorly in certain sequence contexts. To address this problem, Benjamin Thuronyi, core institute member and Merkin Institute of Transformative Technologies in Healthcare director David Liu, and colleagues applied phage-assisted continuous evolution (PACE) to rapidly evolve CBEs that overcome target sequence context constraints and improve activity. The resulting editors are well-suited for a variety of applications and inform a deeper understanding of base editing outcomes in cells. Read the full study in Nature Biotechnology and check out coverage on GenomeWeb.

Varied types of epilepsy may have a common genetic basis

Epilepsy is one of the most widespread neurological disorders, but relatively little is known about the genes involved in its more common forms, and current medications are not effective for about 30 percent of patients. By performing whole exome sequencing for 17,606 people, an international research group, including Yen-Chen (Anne) Feng and instittue member Benjamin Neale of the Stanley Center for Psychiatric Research and the Program in Medical and Population Genetics, with help from Broad’s Hail team, found that more and less severe forms of epilepsy may share similar genetic features. The findings, reported in the American Journal of Human Genetics, could ultimately aid the development of more effective precision medicine strategies. Learn more in a Broad news story. 

Comparing legacy and harmonized TCGA data

Most analyses from The Cancer Genome Atlas (TCGA) have been based on data were aligned with an earlier draft of the reference human genome, GRCh37 (hg19). The National Cancer Institute's Genomic Data Commons, as part of its genomic data harmonization work, aligned or lifted over the legacy TCGA data to the most updated version of the reference genome ― GRCh38 (hg38). Galen Gao, Andrew Cherniack, David Heiman, and Michael Noble of the Broad Cancer Program, and their collaborators, compared the legacy GRCh37 (hg19) TCGA data with their GRCh38 (hg38) versions, for each of the TCGA’s 5 molecular data platforms. They found that the hg19 and hg38 TCGA datasets are very highly concordant. The authors write that their study provides “a rubric that encourages similar comparisons as new data emerge and reference data evolve.” Read more in Cell Systems.

To learn more about research conducted at the Broad, visit broadinstitute.org/publications, and keep an eye on broadinstitute.org/news.