A systems biology look at how the human body changes after birth, key insights into cancer, investigating ancient Iberia, and more.
Research Roundup: March 15, 2019
Welcome to the March 15, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
A data flood from young bloods
For a systems biology look at how the human body changes after birth, a team led by associate member Ofer Levy of Klarman Cell Observatory and Tobias Kollmann (University of British Columbia) analyzed blood samples taken from newborns during the first week of life. They optimized methods to extract transcriptomic, proteomic, metabolomic, cytokine/chemokine, and single cell immune phenotyping data from less than a half-teaspoon worth of blood. The team found dramatic changes occurring along a stable developmental trajectory, especially in interferon and complement pathways and neutrophil-associated signaling. Read more in Nature Communications, the Boston Children’s Hospital blog, Vector, and in Scientific American.
Measuring bacteria that don’t live long or prosper
Screening for new antibiotics that kill drug-tolerant bacteria is difficult using traditional growth inhibition assays. To overcome this challenge, a team led by institute member James Collins, postdoc Jonathan Stokes, and Arnaud Gutierrez of the Infectious Disease and Microbiome Program developed a solid media portable cell killing (SPOCK) assay that uses metabolism-sensitive staining to show the death of antibiotic-tolerant bacteria. Described in Nature Methods, the assay could shed light on how manipulating the metabolic state of bacteria might make antibiotics more effective and help reveal, along with conventional assays, a set of comprehensive targets to treat bacteria in various metabolic states.
A breath of fresh air for histones
Cells react to changing oxygen levels in part thanks to oxygen-sensing feedback loops involving enzymes that add or remove chemical tags called methyl groups to histones (protein structures that help control which genes are active when). What hasn't been clear, however, is whether these enzymes sense oxygen directly or indirectly (through other oxygen-detecting proteins). Writing in Science, postdoc Abhishek Chakraborty, associate member William Kaelin of the Cancer Program, and colleagues report that one such enzyme, KDM6A, does indeed sense oxygen directly, helping clarify the ways in which oxygen sways cell development, especially in embryos (as there is relatively little oxygen in the uterus).
Taking Myc disruption to the Max
The Myc transcription factor is a key player in many cancers, and often works with a second transcription factor called Max to activate growth and proliferation genes. A team led by institute member Angela Koehler — including members of the Cancer Program, Chemical Biology and Therapeutics Science Program, and Center for the Development of Therapeutics — reports in Cell Chemical Biology that a small molecule called KI-MS2-008 encourages copies of Max to bind to each other instead of Myc and reduces tumor growth in both lab and animal models. The findings provide a new strategy for targeting Myc indirectly in cancer.
Charting a path from variant to function
Genome-wide association studies (GWASs) are great at finding genetic variants associated with specific human traits but, from there, identifying “causal” variants and the mechanisms by which they work remains challenging. In Nature Genetics, associated researcher Jacob Ulirsch, graduate students Caleb Lareau and Erik Bao, associate members Jason Buenrostro and Vijay Sankaran, and colleagues applied genetic fine-mapping, an approach to statistically resolve likely causal variants, to 16 measures of blood cell production. They combined these results with a variety of tissue-specific epigenomic datasets to determine potential regulatory mechanisms and cell types of action for hundreds of variants. Learn more in the authors’ tweetorial.
Molecular insight into a rare ovarian cancer
Approximately 20 percent of all human cancers involve mutations in a group of proteins called mSWI/SNF. A team led by postdoc Joshua Pan, institute member Cigall Kadoch, and colleagues studied a rare ovarian cancer called SCCOHT, for which the vast majority of tumors present complete loss of mSWI/SNF ATPase components, SMARCA4 and SMARCA2. The group dissected the role for these components and the complex “module” into which they assemble, revealing their function in gene regulation and the mechanisms underlying SCCOHT oncogenesis. Read more in Nature Genetics and the author’s tweetorial.
Investigating ancient Iberia
In Science, a team led by senior associate member David Reich and colleagues reports new insights about the population history of the Iberian peninsula. The researchers analyzed genomes from 403 ancient Iberians dated between 6000 BC and 1600 AD, 975 ancient people from outside Iberia, and 2,862 present-day people. The most striking discovery suggests that Iberian Y chromosome ancestry was almost completely replaced during the Bronze Age by ancestry originating from the Steppes. The study also includes details regarding genetic variation among ancient hunter-gatherers and intermingling of ancient Iberians with people from North Africa and the Mediterranean. Read more in news stories from Harvard Medical School and The New York Times.