Genetic records of a major migration, an antibiotic's metabolic mechanism, cellular senescence in Down syndrome, and more
By Broad Communications
Credit: Susanna M. Hamilton
Welcome to the January 7, 2022 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Signs of migration
Present-day English and Welsh people harbor more ancestry from a population called Early European Farmers than do modern Scots. To understand why, an international team led by Nick Patterson, Michael Isakov (Harvard), and Program in Medical and Population Genetics senior associate member David Reich examined DNA from nearly 800 pre-Roman individuals from Great Britain and 10 western and central European countries, finding evidence of a major migration into southern Great Britain, likely from France, around 1200 to 800 BCE. Their findings align with theories about when Celtic languages arrived in Great Britain, and also reveal that dairy tolerance spread among Bronze Age Britons earlier than on the continent, suggesting more substantial dairy consumption. Learn more in Nature and the Harvard Gazette.
Imaging-based screens for analysis of DNA repair
Cellular response to DNA damage is critical to survival and development, but the chromatin factors that orchestrate this process are not fully known. Screens used to identify them can be inefficient, with unwanted off-target effects. In Cell Reports, Barbara Martinez-Pastor, Giorgia Silveira, Graham Dellaire, associate member Raul Mostoslavsky of the Epigenomics Program, and colleagues describe two high-throughput imaging platforms for studying the kinetics of DNA repair and protein recruitment to damaged DNA. Using high throughput laser microirradiation and a custom library of chromatin factors, the team identified several new modulators of DNA repair, including the protein PHF20, which is removed from DNA breaks to allow for recruitment of the factor 53BP1.
Uncovering drivers of antibiotic lethality
β-lactam antibiotics treat a range of bacterial infections by inhibiting the activity of enzymes called penicillin-binding proteins, but the link between this mechanism and antibiotic lethality has remained poorly understood. Now, a team led by Michael Lobritz, Ian Andrews, Daniel Dwyer, and institute member James Collins of the Infectious Disease and Microbiome Program (IDMP) has used metabolomics to show that the β-lactam mecillinam works by triggering toxic metabolic shifts in multiple anabolic and catabolic processes. These metabolic shifts include disturbances of peptidoglycan synthesis and protein synthesis, as well as altered ATP utilization and a dysregulated cellular redox environment. Read more in Cell Chemical Biology.
Probing cancer cells with a YAP
Multiple cancers depend on the oncogene YAP1, which helps drive cell proliferation and tumor initiation and is a promising drug target. To better understand YAP1's precise molecular role in cancer, Miju Kim, institute member William Hahn in the Cancer Program, and colleagues conducted a genome-scale genetic rescue screen in YAP1-dependent colon cancer cells. When they suppressed YAP1 expression in these cells, they found that the transcription factor PRDM14 rescued cell proliferation and tumorigenesis by activating the transcription of two additional proteins, CALM2 and SLC2A1. The findings suggest how cancer cells could develop resistance to a YAP1-targeting therapy, and that PRDM14 could be a potential drug target in YAP1-driven cancers. Read more in Developmental Cell.
Microglial metabolism mediators
Cellular metabolism regulates microglial cells' function during brain development, but it’s unclear exactly how. Danyang He (HMS), Orit Rozenblatt-Rosen, core member (on leave) Aviv Regev, institute member Vijay Kuchroo in the Klarman Cell Observatory, and others combined transcriptomic analysis, metabolic profiling, and perturbation studies to demonstrate that microglial phagocytic activity is functionally coupled to the cells’ bioenergetic metabolism. They describe a microglia-astrocyte circuit mediated by the IL-33-ST2-AKT signaling axis that supports microglial metabolic adaptation and function during early brain development. The findings have implications for neurodevelopmental and neuropsychiatric disorders. Read more in Immunity.
Nailing down the role of senescence in Down syndrome
The triplication of chromosome 21 (T21) that drives Down syndrome also induces genome-wide transcriptional disruption. Hiruy Meharena (MIT), senior associate member Li-Huei Tsai in the Cell Circuits Program, and colleagues examined human-derived induced pluripotent stem cells (iPSCs) and iPSC-derived forebrain neural progenitor cells (NPCs) to explore the consequences of T21 on cells' 3D-genome organization, epigenome, and transcriptome. NPCs, but not iPSCs, exhibited changes consistent with alterations seen in senescent cells. Treating T21-harboring NPCs with senolytic drugs alleviated the transcriptional, molecular, and cellular dysfunctions associated with Down syndrome, suggesting these phenotypes may be key in Down syndrome pathogenesis. Read more in Cell Stem Cell.
Home is where the pore is
A microbiome can host numerous strains of a bacterial species, but the environmental parameters that determine how these strains coexist aren't completely understood. In Cell Host & Microbe, Arolyn Conwill (MIT), IDMP associate member Tami Lieberman, and colleagues report that skin anatomy heavily influences strain diversity and geography of Cutibacterium acnes, the most common species on human skin. Using whole genome sequences of C. acnes collected from healthy subjects, they found that individual pores are dominated by lone bacterial strains, dividing C. acnes populations in a way that reduces competition between strains and encourages coexistence. Their findings could impact the design of microbial therapeutics for the skin and other tissues. Learn more in a tweetorial by Conwill.
Molecular and clinical insights to a rare kidney cancer
A limited understanding of the molecular characteristics of translocation renal cell carcinoma (tRCC), an aggressive subtype of kidney cancer, has hindered the development of targeted therapies for this disease. In a study published in Cell Reports, Ziad Bakouny, associate member Eli Van Allen, Toni Choueiri (Dana Farber Cancer Institute), associate member Srinivas Viswanathan of the Cancer Program, and colleagues analyzed genomic and clinical trial data collected from 152 patients with tRCC and highlighted the molecular and clinical features of this cancer. The study findings will help provide a framework for future development and testing of mechanism-driven therapeutic avenues in tRCC.