In Nature this week, a team led by researchers at Yale University School of Medicine report on cis-regulatory control of corticospinal system development and evolution. The team identifies a conserved non-exonic element called E4 that acts as a cortex-specific enhancer for the Fezf2 gene, which is used in the specification of corticospinal neuron identity. "We find that SOX4 and SOX11 functionally compete with the repressor SOX5 in the transactivation of E4," the authors write. "These findings reveal that SOX transcription factors converge onto a cis-acting element of Fezf2 and form critical components of a regulatory network controlling the identity and connectivity of corticospinal neurons."
Also in Nature this week, researchers in California and New York describe their chemical genetic discovery of targets and anti-targets for cancer polypharmacology. The team used a Ret-kinase-driven Drosophila model of multiple endocrine neoplasia type 2 and kinome-wide drug profiling to find that Ret inhibitor AD57 rescues oncogenic Ret-induced lethality, though related inhibitors confer reduced efficacy and enhanced toxicity. "Drosophila genetics and compound profiling defined three pathways accounting for the mechanistic basis of efficacy and dose-limiting toxicity," the researchers write. "Inhibition of Ret plus Raf, Src, and S6K was required for optimal animal survival, whereas inhibition of the 'anti-target' Tor led to toxicity owing to release of negative feedback."
In Nature Genetics this week, an international team of researchers presents a genome-wide approach for the identification of genetic variants that influence fasting glycemic traits and insulin resistance. Using a joint meta-analysis approach to test associations between fasting insulin and glucose levels while accounting for body-mass index, the team identified six previously unknown loci associated with fasting insulin levels. "Risk variants were associated with higher triglyceride and lower high-density lipoprotein cholesterol levels, suggesting a role for these loci in insulin resistance pathways," the authors write.
Finally in Nature this week, Memorial Sloan-Kettering Cancer Center's Aiming Ren and colleagues report on fluoride ion encapsulation by Mg2+ ions and phosphates in a fluoride riboswitch. The Thermotoga petrophila fluoride riboswitch adopts "a higher-order RNA architecture stabilized by pseudoknot and long-range reversed Watson-Crick and Hoogsteen A•U pair formation," the authors write. This structure of the fluoride riboswitch in the bound state "shows how RNA can form a binding pocket selective for fluoride, while discriminating against larger halide ions," the team adds.