Delving into anti-inflammatory molecular crosstalk, heart-stopping genetics, prostate cancer drug resistance, and more
Research Roundup: November 22, 2019
Welcome to the November 22, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Molecular structure resolved, leaving researchers less BAFfled
Approximately 20 percent of all human cancers involve mutations in a group of proteins called BAF, a complex that is also linked to intellectual disability and autism spectrum disorders. However, little has been known about the structure of these complexes and how they contribute to disease. Reporting in Cell, Alfredo Valencia, institute member and Epigenomics Program co-director Cigall Kadoch, and colleagues examined the molecular, structural, and regulatory roles of mutations in the C-terminal domain (CTD) of the SMARCB1 subunit of BAF. Studying mutations associated with the intellectual disability disorder Coffin-Siris syndrome and cancers, the researchers helped uncover an evolutionarily conserved structural role for the SMARCB1 CTD that is perturbed in human disease.
Finding the T cells that matter
T cells are able to home in on a wide range of targets, from viruses to cancer cells, in a specific way thanks to specific sequences in receptors on their surfaces called T cell antigen receptors (TCRs). Chris Love and Wayne Shreffler, who are part of Broad’s Food Allergy Science Initiative (FASI), institute member Alex Shalek, and their colleagues have developed a new method using single cell RNA sequencing (scRNA-seq) that can determine those TCR sequences along with the corresponding full transcriptomes. This technique allows researchers to identify T cell subpopulations that have the same target. The team showed that they could identify T cells with common TCRs in mice and in patients with food allergy, and are now using their method to study how patients’ T cells respond to treatments for peanut allergies. Read more in Nature Immunology and MIT News.
Some patients with advanced prostate cancer develop resistance or never respond to treatment with androgen-receptor (AR) inhibitors. A team led by Justin Hwang and institute member William Hahn of the Broad's Cancer Program and Ji-Heui Seo (DFCI) performed a genome-scale open reading frame screen in androgen-dependent prostate cancer cells exposed to the AR inhibitor enzalutamide. In Cell Reports, they describe how integrating information from the genomics and transcriptomics of metastatic castration-resistant prostate cancers revealed that the transcription factor CREB5 is a mediator of enzalutamide resistance. The work underscores the role of AR signaling in prostate cancer and suggests that CREB5 could be a potential therapeutic target.
The genetics underlying sudden cardiac death
“Sudden cardiac death” kills roughly 220,000 US adults annually, the majority of whom have no prior symptoms of a heart issue. A team led by Program in Medical and Population Genetics associated scientist Amit Khera and colleagues has identified rare pathogenic DNA variants, in 49 genes, that can predispose individuals to four important causes of sudden cardiac death. The team hopes these results can help identify asymptomatic patients who are at a higher risk of sudden cardiac death due to their genetics. Check out the full story in Journal of the American College of Cardiology, and read more in a press release from Massachusetts General Hospital and news coverage in WBUR.
Putting the brakes on inflammation
When the body mistakenly reacts to an environmental stimulus, the allergic response usually includes some type of inflammation. Interactions between the nervous system and the immune system appear to regulate this process, but the cell types and mechanisms involved aren’t fully understood. Two studies in Immunity — one led by Heping Xu, Jiarui Ding, core institute member and Klarman Cell Observatory director Aviv Regev, and core institute member and Immunology Program director Ramnik Xavier; the other by Antonia Wallrapp, Patrick Burkett, Samantha Riesenfeld, Regev, and institute member Vijay Kuchroo — recently uncovered a new type of molecular crosstalk between these systems, in the lung and intestine in mice, in a cellular circuit that suppresses inflammation. The work, funded in part by FASI, adds to the emerging picture of how cells keep inflammation in check when they encounter environmental triggers, and could someday help discover new treatments for allergies. Read more in a Broad news story.