Volume 48 Issue 5, May 2016

A new mouse model linking diabetes, insulin secretion and autoimmunity with a high-fat diet supports a shared mechanism for type 1 (T1D) and type 2 (T2D) diabetes. In this model, the protein secretion system of insulin-producing pancreatic beta cells is stressed, leading to increased beta cell apoptosis and diabetes via reduced levels of the transcription factor GLIS3, a pathogenic pathway that can be mimicked by a high-fat diet.

How maternal diet influences offspring metabolism is unclear, as it is difficult to distinguish between the effects of the in utero environment and epigenetic factors contributed by the oocyte. In a mouse model of high-fat diet, a new study teases apart these mechanisms by using in vitro fertilization and shows that susceptibility of offspring to metabolic disorder can likely be attributed to epigenetic inheritance via the oocyte.

Determining how the evolving genome-wide map of distal regulatory elements is connected with target genes has remained a significant challenge, despite progress in understanding chromatin architecture and regulation. A new study presents a computational approach for predicting distal element–gene interactions.

Jian Yang and colleagues propose a method that integrates summary data from GWAS and eQTL studies to identify genes whose expression levels are associated with complex traits because of pleiotropy. They apply the method to five human complex traits and prioritize 126 genes for future functional studies.

Sean Whalen and colleagues present a computational method, TargetFinder, for reconstructing three-dimensional regulatory landscapes using one-dimensional genomic features. TargetFinder identifies the minimal set of features necessary to predict individual interacting enhancer–promoter pairs and accurately distinguishes them from non-interacting pairs.

Johannes Beckers, Martin Hrabě de Angelis and colleagues use in vitro fertilization to demonstrate epigenetic germline inheritance of acquired metabolic disorders in mice. They show that a parental high-fat diet renders offspring more susceptible to developing obesity and diabetes.

Hidewaki Nakagawa and colleagues report a comprehensive genome-wide mutational landscape of 300 liver cancers from Japanese individuals. They identify candidate driver mutations, including ones in noncoding regions, and structural mutations affecting the expression of nearby genes.

David Ellinghaus and colleagues report a combined association analysis of five chronic inflammatory diseases. They identify 27 new associations and highlight disease-specific association patterns at shared susceptibility loci.

Adrian Liston and colleagues use a transgenic mouse model to demonstrate that beta cell failure is a mechanistic commonality in type 1 and type 2 diabetes. They find that the changes in the molecular pathways identified as contributing to beta cell loss are paralleled in human islets from patients with type 2 diabetes.

Nadav Ahituv, Nicola Illing, Jeff Wall and colleagues sequence the genome of the bat Miniopterus natalensis and perform RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages. Their analyses identify genomic regions that may contribute to bat wing formation.

Bin Zhou and colleagues use genetic labeling in mice to show that endocardial cells of the sinus venosus substantially contribute to the liver vasculature, which thus shares a common developmental origin with coronary arteries. Inhibition of endocardial angiogenesis leads to reduced endocardial contribution to the liver vasculature and to defects in liver organogenesis.

Alexander Pym, Ashlee Earl and colleagues use the whole-genome sequences from 498 strains of Mycobacterium tuberculosis to identify new genotypes conferring resistance to antitubercular drugs. They find that loss-of-function mutations in ald (Rv2780), encoding L-alanine dehydrogenase, are associated with unexplained drug resistance and demonstrate that these mutations confer resistance to D-cycloserine.

Elise Robinson, Mark Daly and colleagues present an analysis of genetic data from autism spectrum disorder (ASD) and population-based studies and find evidence for genetic correlations between ASDs and typical variation in social behavior and communication traits. These results may inform genetic models of ASDs and other neuropsychiatric disorders.

Chiea Chuen Khor, Tin Aung and colleagues report the results of a large genome-wide association study of primary angle closure glaucoma. They identify five new susceptibility loci and provide insights into disease pathogenesis.

Meredith Yeager, Stephen Chanock and colleagues analyze mosaic loss of the Y chromosome in three prospective cohorts and observe association with age and smoking but not with cancer survival. They also identify common variation at TCL1A associated with increased risk of mosaic loss of the Y chromosome.

Hiroyuki Mano and colleagues report fusions involving DUX4 in 16.4% of Ph-negative adolescent and young adult acute lymphoblastic leukemia (AYA-ALL) cases. Transplantation assays in mice support an oncogenic role for the DUX4-IGH fusion gene, which expresses DUX4 protein with an aberrant C terminus at high levels in patients with AYA-ALL.

Douglas Epstein and colleagues use de novo motif analysis to identify sequence motifs and cognate transcription factors for brain enhancers of Shh active in the zona limitans intrathalamica (zli). They find new zli enhancers in mice and a functional equivalent in hemichordates, indicating an ancient origin of these sequence elements.

James Collins and colleagues explore the role of the bacterial epigenome in antibiotic stress survival. They find that Escherichia coli survival under antibiotic pressure is strongly compromised in the absence of adenine methylation at GATC sites, suggesting that targeting adenine methylation might be a viable approach to enhance antibiotic activity.