In PLOS Genetics, researchers from the University of Groningen and elsewhere describe histone H3.3 mutations that coincide with genomic instability in pediatric high-grade glioma brain cancer, focusing on an "oncohistone" called H3.3K27M. Using copy number variant (CNV) profiling on 745 pediatric high-grade gliomas, single-cell whole-genome sequencing on cells from three H3.3K27M-containing tumors, and experiments on cell lines with inducible versions of H3.3K27M, the team found that the oncohistone corresponded with higher-than-usual CNV levels, altered gene regulation, enhanced replication stress sensitivity, and other changes linked to increased genomic instability. "Together, our data uncover a role for H3.3 in DNA replication under stress conditions that is altered by the K27M mutation, promoting genomic instability and potentially glioma development."
Investigators in China and Canada outline a pig model of cardiovascular disease (CVD) in another paper in PLOS Genetics. The team turned to CRISPR/Cas9-based gene editing to develop Bama miniature pig models deficient for the cardiovascular disease-related gene ASGR1, following organ function-related blood markers, levels of blood lipids such as high-density lipoprotein (HDL) or non-HDL cholesterol, and other features in the model animals of time. "Our results highlight the demand for taking advantage of genetically modified large animal models to investigate the pathogenesis and therapeutic development of CVD in humans," the authors write, adding that "we demonstrate the first link between ASGR1 deficiency and liver injury, a feature that has not been documented in humans with ASGR1 variants."
A Cedars-Sinai Medical Center-led team characterizes regulatory and other features in colorectal tumor precursor polyps for a paper in PLOS One. With array-based protein expression profiling on 625 colorectal adenoma polyps and 142 serrated lesion polyps from more than 550 patients with one or both precursor types who were treated at nine North American centers from 1994 to 1998, the researchers assessed proliferation, apoptosis, and regulatory features, uncovering regulatory and other differences between the tumor precursors. "Our findings emphasize the complexity and heterogeneity between adenomas and serrated lesions," the authors report. "From a clinical perspective, understanding underlying mechanistic differences between precursors to adenocarcinoma in the colon, may provide greater insight into which lesions should be followed clinically."