Articles in 2015

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

Cannabinoid-induced feeding signals are shown to enhance pro-opiomelanocortin (POMC) neuronal activity in mice, causing an enhancement of β-endorphin release, which is crucial in causing this cannabinoid-induced response; these results uncover an overlooked role of hypothalamic POMC neurons in the promotion of feeding by cannabinoids.

Lineage-specific transcription factors and signalling pathways cooperate with pluripotency regulators to control the transcriptional networks that drive cell specification and exit from an embryonic stem cell state; here, we report genome-wide binding data for 38 transcription factors combined with analysis of epigenomic and gene expression data during the differentiation of human embryonic stem cells into the three germ layers.

The bacterial CRISPR/Cas system acquires short phage sequences known as spacers that integrate between CRISPR repeats and constitute a record of phage infection; this study shows that the Cas1–Cas2 complex is the minimal machinery required for spacer acquisition and the complex integrates oligonucleotide DNA substrates into acceptor DNA in a manner similar to retroviral integrases and DNA transposases with Cas 1 as the catalytic subunit and Cas2 acting to increase integration activity.

The crystal structure of the RAG1–RAG2 heterotetramer forms a Y-shaped structure, with each arm containing a RAG1–RAG2 heterodimer; the overall structure is reminiscent of hairpin-forming transposases, attesting to its evolutionary history as a specialized form of a transposition activity.

Bacterial CRISPR–Cas loci acquire short phage sequences called spacers that integrate between DNA repeats and how these viral sequences are chosen was unknown; in these studies of the type II CRISPR–Cas system of Streptococcus pyogenes, the Cas9 nuclease known to inactivate invading viral DNA was found to be required for the selection of functional spacers during CRISPR immunity.

An analysis of genome-wide chromatin interactions during human embryonic stem cell differentiation reveals changes in chromatic organization and simultaneously identifies allele-resolved chromatin structure and differences in gene expression during differentiation.

Genome-wide association meta-analyses of waist-to-hip ratio adjusted for body mass index in more than 224,000 individuals identify 49 loci, 33 of which are new and many showing significant sexual dimorphism with a stronger effect in women; pathway analyses implicate adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution.

A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis.

Comprehensive genome sequencing of 120 individuals representing all of the Darwin’s finch species and two close relatives reveals important discrepancies with morphology-based taxonomy, widespread hybridization, and a gene, ALX1, underlying variation in beak shape.

Grid cells are cells of the brain’s internal map of space that fire when an animal is in a location corresponding to the vertices of a hexagonal grid pattern tiling the entire environment; how the pattern is mapped onto the external environment has remained a mystery, however, new studies in rat reveal that the axes of the grid are determined by the boundaries of the external environment and provide insight into the rotation of the grid axis in relation to these boundaries.

An analysis of a bacterial homologue of the human glutamate transporter using single-molecule FRET and X-ray crystallography reveals that opening of the interface between its distinct transport and scaffold domains is rate determining for the transport cycle.

Mediator is the key transcription co-activator complex that enables basal and regulated transcription initiation by RNA polymerase (Pol) II; here a 15-subunit yeast core Mediator bound to a core Pol II initiation complex is reconstituted and its structure determined by cryo-electron microscopy at subnanometre resolution.

A new record of Pliocene carbon dioxide variations derived from boron isotopes shows that climate sensitivity (the change in global mean temperature in response to radiative forcing) during the Plio-Pleistocene does not vary when cycles in continental ice are taken into account; this suggests that current estimates can be used to predict future climate.

A study of the effect of radiative forcing, climate feedback and ocean heat uptake on global-mean surface temperature indicates that overestimation of the response of climate models to radiative forcing from increasing greenhouse gas concentrations is not responsible for the post-1998 discrepancy between model simulations and observations.

The Cancer Genome Atlas presents an integrative genome-wide analysis of genetic alterations in 279 head and neck squamous cell carcinomas (HNSCCs), which are classified by human papillomavirus (HPV) status; alterations in EGFR, FGFR, PIK3CA and cyclin-dependent kinases are shown to represent candidate targets for therapeutic intervention in most HNSCCs.

The emRiboSeq sequencing method is used to track polymerase activity genome-wide in vivo; despite Okazaki fragment processing, DNA synthesized by error-prone polymerase-α (Pol-α) is retained in vivo and comprises ∼1.5% of the genome, establishing Pol-α as an important source of genomic variability and providing a mechanism for site-specific variation in nucleotide substitution rates.

The facile synthesis of a stable Au(III) cationic complex is described; this gold catalyst exhibits hard, oxophilic Lewis acidity, enabling selective conjugate additions and a [2 + 2] cycloaddition reaction.

Essential enzymes in genetically modified organisms are computationally redesigned to functionally depend on non-standard amino acids, thereby achieving biocontainment with unprecedented resistance to escape by evolution or by supplementation with environmental metabolites.

Using single-particle electron cryomicroscopy, several structures are reported which illuminate the mechanisms of action of the ATPase NSF that disassembles the SNARE complex into individual protein components.