Articles in 2010

As part of the modENCODE initiative, which aims to characterize functional DNA elements in D. melanogaster and C. elegans, this study uses RNA-Seq, tiling microarrays and cDNA sequencing to explore the transcriptome in 30 distinct developmental stages of the fruitfly. Among the results are scores of new genes, coding and non-coding transcripts, as well as splicing and editing events.

As part of the modENCODE initiative, which aims to characterize functional DNA elements in D. melanogaster and C. elegans, this study presents a genome-wide chromatin landscape of the fruitfly, based on 18 histone modifications. Nine prevalent chromatin states are described. Integrating these analyses with other data types reveals individual characteristics of different genomic elements. The work provides a resource of unprecedented scale for future experimental investigations.

Impulsive behaviour characterizes several psychiatric diseases and violent behaviour but its origins are complex. Here, exon sequencing focused on fourteen serotonin- and dopamine-related genes identified a mutation in HTR2B, which was associated with psychiatric diseases marked by impulsivity in a Finnish population. The role of this serotonin receptor in impulsivity is further supported by the knockout mouse phenotype.

Using DNA from a finger bone, the genome of an archaic hominin from southern Siberia has been sequenced to about 1.9-fold coverage. The group to which this individual belonged shares a common origin with Neanderthals, and although it was not involved in the putative gene flow from Neanderthals into Eurasians, it contributed 4–6% of its genetic material to the genomes of present-day Melanesians. A tooth whose mitochondrial genome is very similar to that of the finger bone further suggests that these hominins are evolutionarily distinct from Neanderthals and modern humans.

To investigate the core engine of the eukaryotic mitotic cycle, a minimal control network has been generated in fission yeast that efficiently sustains cellular reproduction. Orderly progression through the major events of the cell cycle is driven by oscillation of an engineered minimal CDK module lacking much of the canonical regulation.

Analysing single cells from human B-cell acute lymphoblastic leukaemias, this study maps the genetic heterogeneity of cells within a given tumour sample, the evolutionary path by which different subclones have emerged, and ongoing dynamic changes associated with relapse. Leukaemia-propagating 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-propagating cells.

A crystal structure of the tandem PHD and bromodomain regions of the transcription and chromatin regulator TRIM24 reveals combinatorial recognition of dual marks on the histone H3 tail. TRIM24 is involved in activation of oestrogen-dependent genes and is aberrantly expressed in breast cancer.

β-adrenergic receptor signalling in adipocytes stimulates energy expenditure via cAMP-dependent increases in lipolysis and fatty-acid oxidation, and this signalling mechanism is thought to be disrupted in obesity. Here, the cAMP-responsive CREB coactivator Crtc3 is shown to promote obesity in mice by attenuating β adrenergic receptor signalling in adipose tissue.

Humans and animals readily learn to associate neutral cues paired with rewards, but the exact role that dopamine release has in this learning is controversial. Using previously established rat strains selectively bred for many generations to have greater or lesser propensity to assign value to learned cues, this study uses cyclic voltammetry to measure dopamine signals in the different strains and also examines the effect of blocking dopamine. It is concluded that dopamine selectively mediates motivational, rather than predictive, aspects of the cues.

Haematopoietic stem cells (HSCs) are very sensitive to energetic and oxidative stress, and modulation of the balance between their quiescence and proliferation is needed to respond to metabolic stress while preserving HSCs' long-term regenerative capacity. Here the tumour suppressor Lkb1 is shown to promote stem-cell maintenance and tissue regeneration by regulating energy metabolism and by preventing aneuploidy.

Haematopoietic stem cells (HSCs) are very sensitive to energetic and oxidative stress, and modulation of the balance between their quiescence and proliferation is needed to respond to metabolic stress while preserving HSCs' long term regenerative capacity. Here the tumour suppressor Lkb1 is shown to have a crucial role in maintaining energy homeostasis in haematopoietic cells — an effect largely independent of AMPK and mTOR signalling.

It is shown that amyloid-β oligomers interact with the receptor tyrosine kinase EphB2 and trigger its degradation. EphB2 regulates NMDA-type glutamate receptors and its depletion in normal mice reduces NMDA receptor currents and impairs long-term potentiation, both of which are important for memory formation. Increasing EphB2 levels in a mouse model of Alzheimer's disease improves memory.

In cells, WAVE protein, a central regulator of actin dynamics during cell motility, is constitutively incorporated into WAVE regulatory complex (WRC), is normally present in an inactive state and can be activated by a number of inputs. These authors present the structure and mechanistic analysis of WRC. The combined data reveal how the WAVE protein is inhibited within the WRC complex and provide mechanisms for WRC activation at the plasma membrane.

Sugar efflux transporters are essential for diverse processes such as nectar production and seed and pollen development, as well for the maintenance of blood glucose levels in animals. These authors identify and characterize a novel sugar transporter family, SWEET, and show that several Arabidopsis, rice and metazoan homologues mediate glucose transport. In addition, some of these transporters are exploited by plant pathogens for nutritional gain and virulence.

The first crystal structure for an arenavirus nucleoprotein is solved, revealing some new functions. The C-terminal domain has 3′ to 5′ exonuclease activity, and it is confirmed that Lassa virus nucleoprotein is capable of cleaving short RNAs and suppressing virus-induced interferon induction. The N-terminal domain contains a unique cap-binding feature, which has implications for understanding the distinctive cap-snatching mechanism of arenaviruses.

Cysteine is the most intrinsically nucleophilic amino acid in proteins, but the absence of a consensus sequence that defines functional cysteines in proteins has hindered their discovery and characterization. Here, a proteomics method to quantitatively profile the intrinsic reactivity of cysteine residues directly in native biological systems is described. Hyper-reactive cysteines were identified in several proteins of uncharacterized function, including a residue conserved across eukaryotes that is shown to be required for yeast viability and involved in iron–sulphur protein biogenesis.

tRNAs are synthesized in a premature form that requires trimming of the 5′ and 3′ ends and modification of specific nucleotides. RNase P, a complex containing a long catalytic RNA and a protein cofactor, catalyses the cleavage that generates the mature 5′ end. Here, the structure of RNase P bound to mature tRNA^Phe is solved. Recognition of the leader sequence and its mechanism of cleavage is determined by soaking an oligonucleotide corresponding to the premature 5′ end into the crystal.

Light sensing outside the eyes is common in many animals but is usually confined to specialized organs. Here, the entire body wall of the fruitfly larva is found to be tiled with blue- and ultraviolet-light sensing neuronal dendrites, which are essential for the larva's innate light-avoidance behaviour. The phototransduction machinery used by these neurons is distinct from other Drosophila photoreceptor molecules but similar to a system recently identified in nematode neurons.

Mutations in the methyl-CpG-binding protein 2 (MeCP2) gene cause Rett syndrome, a neurodevelopmental disorder with features of autism. Multiple mouse models of MeCP2 have been generated, but show only a subset of the symptoms of Rett syndrome. These authors find that mice with selective deletion of MeCP2 in GABA-mediated neurons show not only impaired GABA-mediated function, but capitulate multiple key features of Rett, further suggesting a role of inhibitory function in neuropsychiatric disease.