Research Roundup: November 13, 2020

A massive mammalian catalog, tracking transcription factor locations, cancer drugs' multiple mechanisms, and more

Susanna M. Hamilton
Credit: Susanna M. Hamilton

Welcome to the November 13, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Zoonomia Project: the largest set of mammalian genomes to date 

An international team of researchers called the Zoonomia Consortium — led at Broad by Diane Genereux, Kerstin Lindblad-Toh, and Elinor Karlsson of the Vertebrate Genomics Group — has analyzed and compared whole genomes representing more than 80 percent of all mammalian families, spanning almost 110 million years of evolution. Their genomic dataset, which is aimed at advancing both human health research and biodiversity conservation, includes genomes from more than 120 species that were not previously sequenced, captures mammalian diversity at an unprecedented scale, and also reveals species at risk of extinction. Learn more in Nature and in a Broad news story

Location, location, location

The transcription factor TFEB acts as a sensor and signal for the cell to produce lysosomes, which help cells recycle old or unneeded cellular components and ingested pathogens. Because breakdowns in TFEB and lysosome function are linked to metabolic, neurological, and infectious diseases, Kim Carey, Geraldine Paulus, core institute member and Immunology Program director Ramnik Xavier, and colleagues set out to identify all of the cellular circuits TFEB directs. They found that TFEB's transcriptional impacts depend heavily on its location within the cell, as well as its stimulation state, and that its influence is held in check by the genes BHLHE40 and BHLHE41. Learn more in Cell Reports.

Multifunctional medications

Drugs that block CDK4/6 were designed to trigger cell cycle arrest in cancer cells, but seem to impact cancer cell biology in a number of other ways as well. Using lab models and clinical specimens, a team led by Henry Long (DFCI), Cancer Program associate member Jean Zhao, and Shom Goel (MacCallum Cancer Centre) have found that these compounds dramatically remodel cancer cells' chromatin landscape, in the process activating a broad range of enhancers and super-enhancers. These enhancers' influence explains many of the drugs' additional effects, including changes in immunogenicity, apoptotic responses, and differentiation. Their findings, the team writes in Nature Cancer (paywall), could guide further work on CDK4/6 inhibitors.

Mapping protein turnover

The levels of specific proteins within a cell change frequently as the cell carries out its functions. A complex network of enzymes controls the composition of this mixture, degrading proteins when they are no longer needed. To better understand this cellular machinery, a team supervised by associate members Robert Farese and Tobias Walther of the Metabolism Program developed a platform that combines quantitative measures of protein turnover with systematic gene deletions, and tested it in the yeast Saccharomyces cerevisiae. The resulting turnover map (T-MAP) provides a new resource for identifying and mechanistically dissecting the ubiquitin-mediated protein degradation system. Learn more in Cell Reports.

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