HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment

Physical properties of naked DNA influence nucleosome positioning and correlate with transcription start and termination sites in yeast

Abstract Background In eukaryotic organisms, DNA is packaged into chromatin structure, where most of DNA is wrapped into nucleosomes. DNA compaction and nucleosome positioning have clear functional implications, since they modulate the accessibility of genomic regions to regulatory proteins. Despite the intensive research effort focused in this area, the rules defining nucleosome positioning and the location of DNA regulatory regions still remain elusive. Results Naked (histone-free) and nucleosomal DNA from yeast were digested by microccocal nuclease (MNase) and sequenced genome-wide. MNase cutting preferences were determined for both naked and nucleosomal DNAs. Integration of their sequencing profiles with DNA conformational descriptors derived from atomistic molecular dynamic simulations enabled us to extract the physical properties of DNA on a genomic scale and to correlate them with chromatin structure and gene regulation. The local structure of DNA around regulatory regions was found to be unusually flexible and to display a unique pattern of nucleosome positioning. Ab initio physical descriptors derived from molecular dynamics were used to develop a computational method that accurately predicts nucleosome enriched and depleted regions. Conclusions Our experimental and computational analyses jointly demonstrate a clear correlation between sequence-dependent physical properties of naked DNA and regulatory signals in the chromatin structure. These results demonstrate that nucleosome positioning around TSS (Transcription Start Site) and TTS (Transcription Termination Site) (at least in yeast) is strongly dependent on DNA physical properties, which can define a basal regulatory mechanism of gene expression

GABA-B1 Receptor-Null Schwann Cells Exhibit Compromised In Vitro Myelination

GABA-B receptors are important for Schwann cell (SC) commitment to a non-myelinating phenotype during development. However, the P0-GABA-B1fl/fl conditional knockout mice, lacking the GABA-B1 receptor specifically in SCs, also presented axon modifications, suggesting SC non-autonomous effects through the neuronal compartment. In this in vitro study, we evaluated whether the specific deletion of the GABA-B1 receptor in SCs may induce autonomous or non-autonomous cross-changes in sensory dorsal root ganglia (DRG) neurons. To this end, we performed an in vitro biomolecular and transcriptomic analysis of SC and DRG neuron primary cultures from P0-GABA-B1fl/fl mice. We found that cells from conditional P0-GABA-B1fl/fl mice exhibited proliferative, migratory and myelinating alterations. Moreover, we found transcriptomic changes in novel molecules that are involved in peripheral neuron-SC interaction