Articles in 2011

In geographic atrophy, a type of macular degeneration, retinal pigmented epithelium (RPE) cells die. This paper finds that DICER1, which processes miRNA precursors, is reduced in RPE from individuals with geographic atrophy. Cell death is not due to loss of miRNA processing, however; rather, the absence of DICER1 allows accumulation of pathological Alu repeat sequence RNAs. This work reveals a novel function of Dicer in degrading Alu RNAs.

When an extrasolar planet passes in front of its star (transits), its radius can be measured from the decrease in starlight and its orbital period from the time between transits. This study reports Kepler spacecraft observations of a single Sun-like star that reveal six transiting planets, five with orbital periods between 10 and 47 days plus a sixth one with a longer period. The five inner planets are among the smallest for which mass and size have both been measured, and these measurements imply substantial envelopes of light gases.

Harnessing information from whole genome sequencing in 185 individuals, this study generates a high-resolution map of copy number variants. Nucleotide resolution of the map facilitates analysis of structural variant distribution and identification of the mechanisms of their origin. The study provides a resource for sequence-based association studies.

Reprogramming of somatic cells to induce pluripotent cellular properties that closely resemble those of embryonic stem (ES) cells has important therapeutic potential. The first whole genome single-base resolution profiling of the DNA methylomes of several human ES cell, induced pluripotent stem cell (iPSC) and somatic progenitor lines shows that iPSCs are fundamentally distinct from ES cells, insofar as they manifest common, quantifiable epigenomic differences. These 'hotspots of aberrant reprogramming' might be potentially useful as diagnostic markers for incomplete iPSC reprogramming, for the characterization of the efficacy of different reprogramming techniques, and for screening the potential propagation of altered methylation states into derivative differentiated cells.

In humans, vulnerability to tobacco addiction has been linked to variations in the gene encoding the α5 nicotinic acetylcholine receptor subunit, but the functional mechanisms linking gene to behaviour are unknown. Using a combination of knockout mice, lentiviral rescue, and RNAi knockdown in rats, this study shows that manipulating the levels of this subunit alters the drive to obtain nicotine, particularly at high doses that are aversive to wild-type animals. Furthermore, these subunits are implicated in the projection between medial habenula and interpeduncular nucleus in integrating negative side effects of high doses of nicotine and reward signals. It is proposed that this projection provides a negative motivational signal that limits nicotine consumption.

Circadian clocks are critical timing regulators of physiology and behaviour that are ubiquitous in eukaryotes. Most mechanistic models of the this clock are based on transcription cycles, but some evidence for post-translational regulation has recently surfaced in plants and cyanobacteria. This is one of two groups demonstrating a role for the oxidation of peroxiredoxin proteins in maintaining an entrainable oscillation in human red blood cells and a unicellular alga. These data indicate a role for non-transcriptional mechanisms in clock models and open the door to future work exploring the connections between the transcriptional and non-transcriptional circadian machinery.

The standard view of the genome is that the two DNA strands are linked by Watson–Crick base pairing. Some deviations from this canonical pairing have been observed when DNA is bound to a ligand. This paper now shows that naked DNA itself can transiently adopt a Hoogsteen base-pairing arrangement. This excited state base pairing provides a means to expand the chemistry and structure of DNA, and has implications for the binding of proteins to and repair of DNA.

After learning, memories are strengthened through a process called 'consolidation', which requires new gene and protein expression, rendering new information less vulnerable to disruption. Several transcription factor families are involved in this process, but many of the relevant downstream targets are unknown. Here, IGF-II, a protein typically implicated in somatic tissue growth and repair, is identified as an essential factor in memory retention. IGF-II initiates its own network of signalling cascades that can lead to synaptic potentiation and are most effective within a short time frame immediately after learning. Thus, IGF-II represents an endogenous target for potentially modulating cognitive enhancement.

A novel technique called native elongating transcript sequencing (NET-seq) is described, which can quantify transcription with single nucleotide resolution. It is based on sequencing nascent transcripts associated with RNA polymerase II that are captured directly from live cells, and is used to gain insights into polymerase pausing and backtracking and the directionality of transcription.

Analysing human B-cell acute lymphoblastic leukaemias, this study maps the genetic heterogeneity of cells within a given tumour sample and the evolutionary path by which different subclones have emerged. Leukaemia-initiating cells that transplant the disease mirror the genetic variegation of the bulk tumours, providing insights into the heterogeneity of these functional subpopulations at the genetic level. This has implications for therapeutic approaches targeting the tumours and specifically leukaemia-initiating cells.

The X-ray crystal structure of the human β₂ adrenergic receptor, a G-protein-coupled receptor, in an agonist-bound 'active' state is solved. Comparison of this structure with a previously published structure of the same GPCR in an inactive state indicates that minor changes in the binding pocket of the protein lead to major changes elsewhere — there is a large outward movement of the cytoplasmic end of one of the transmembrane segments and rearrangements of two other transmembrane segments. This structure provides insights into the process of agonist binding and activation.

Nitrogen-fixing rhizobia use lipochitooligosaccharide (LCO) signal molecules to initiate a symbiotic relationship with plant roots. Although it has been suggested that mycorrhizal fungi also secrete chemical signals for this process, the identity of these molecules was unknown. It is now shown that like rhizobia, mycorrhizal fungi produce LCOs and that these molecules are important for the establishment of the symbiotic relationship between plant root and fungus.