Letters in 2010

Identifying the genomic regulatory sequences, such as enhancers, that control early embryonic development remains a difficult challenge. Here, profiling of histone modifications and chromatin regulators in human embryonic stem cells (hESCs) reveals unique signatures that are used to identify over 2,000 putative enhancers. These enhancers are either active in the h ESCs or associated with early developmental genes.

The first X-ray crystal structure of a diterpene cyclase is reported — this enzyme, taxadiene synthase, catalyses the cyclization of an isoprenoid in the first committed step of the biosynthesis of the cancer chemotherapeutic drug Taxol. The C-terminal catalytic domain binds and activates the substrate in a manner seen in class I terpenoid cyclases, but the N-terminal domain and a third 'insertion' domain together adopt the fold of a class II terpenoid cyclase. It is proposed that this enzyme could be the ancestral progenitor of all terpenoid cyclases.

Studies have indicated an undefined role in DNA replication for CENP-B, a DNA binding protein associated with heterochromatin, centromeres and retrotransposon long terminal repeats (LTRs). Here it is shown that Sap1, which binds LTRs, promotes genomic instability when CENP-B activity is absent. CENP-B facilitates replication fork progression through LTRs in a way that protects against rearrangements.

Saturn's rings are more than 90–95% water ice, which implies that initially they were almost pure ice because they are continually polluted by rocky meteoroids. Saturn has only one large satellite, Titan, whereas Jupiter has four large satellites; additional large satellites probably existed originally but were lost as they spiralled into Saturn. Now, numerical simulations of the tidal removal of mass from a differentiated, Titan sized satellite as it migrates inward towards Saturn are reported. Planetary tidal forces preferentially strip material from the satellite's outer icy layers, while its rocky core remains intact and is lost to collision with the planet. The result is a pure ice ring.

Using a temporal series of growth factor manipulations to mimic embryonic intestinal development in culture, this study has successfully directed the differentiation of human pluripotent stem cells (both embryonic stem cells and induced pluripotent stem cells) into intestinal tissue. This approach may provide therapeutic benefit for disease studies.

The TET family of enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Mutations in the gene encoding TET2 are frequently observed in myeloid malignancies. Here it is shown that these disease-associated mutations compromise TET2 catalytic activity; bone marrow samples from patients with TET2 mutations have low levels of 5hmC in genomic DNA, and TET2 is required for normal haematopoietic differentiation. Measurement of genomic 5hmC levels may prove valuable as a diagnostic tool in myeloid cancers.

Observations of the 21-centimetre line of atomic hydrogen in the early Universe directly probe the history of the reionization of the gas between galaxies. If reionization happened rapidly, there will be a characteristic signature visible against the smooth foreground in an all-sky spectrum. Here, an all-sky average spectrum between 100 and 200 MHz is reported, corresponding to the redshift range 6 < z < 13 for the 21-centimetree line. The data exclude a rapid reionization timescale of Δz < 0.06 at the 95% confidence level.

For synthetic biologists' creativity to be unleashed, basic circuits must become truly interchangeable, that is, modular and scalable. This study, one of two linked papers, has harnessed yeast pheromone communication to achieve complex computation through communication between individual cells performing simple logic functions. Such extracellular 'chemical wiring' is one promising way to get around intracellular noise when building more complex genetic circuitry.

Medulloblastomas are the most common malignant childhood brain tumours and are thought to arise from the cerebellum. There is substantial heterogeneity among medulloblastomas and some are thought to arise following aberrant Sonic Hedgehog pathway activation. It is now shown that a distinct subtype of medulloblastoma arises from the dorsal brainstem and is associated with altered WNT signalling. Distinct molecular and clinical profiles of the subtypes have implications for future treatment.

A primordial carbon-to-oxygen ratio (C/O) greater than 0.8 in an exoplanet causes a carbide-dominated interior, as opposed to the silicate-dominated composition found on Earth; the atmospheres also can differ from those in the Solar System. The solar C/O is 0.54. This study reports an analysis of spectra from the transiting hot Jupiter WASP-12b that reveals that C/O>1 in its atmosphere, based upon the observed concentrations of the prominent molecules CO, CH₄ and H₂O.

High-contrast near-infrared imaging of the nearby star HR 8799 has shown three giant planets. Here, the presence of a fourth planet, interior to and about the same mass as the other three, is reported. The system, with this additional planet, represents a challenge for current planet formation models as none of them can explain the in situ formation of all four planets.

Increased melting is often assumed to cause acceleration of ice sheets and glaciers through basal lubrication, possibly leading to increased rates of sea level rise. Now a physically-based model challenges this view, illustrating that above a critical threshold, increased melt will suppress the dynamic thinning process. Short-term spikes in water delivery, as from lake drainage or precipitation, still have the potential to generate spikes in velocity, but overall increases in melt do not appear likely to cause velocity increases.

For two hundred years, scientists have noticed that the appearance of embryos in related species converge in their appearance mid-way in development, diverging thereafter. But is this 'phylotypic stage' real, and how is it connected with the genetic basis of development? This issue is looked at in microcosm, concentrating on gene expression during the development of six species of the fruitfly Drosophila. It is shown that the genes expressed during the phylotypic stage are more conserved across the genus, supporting the age-old model.

For synthetic biologists' creativity to be unleashed, basic circuits must become truly interchangeable, that is, modular and scalable. This study, one of two linked papers, has harnessed bacterial 'quorum sensing' to achieve complex computation through communication between individual cells performing simple logic functions. Such extracellular 'chemical wiring' is one promising way to get around intracellular noise when building more complex genetic circuitry.

For two hundred years, scientists have noticed that the appearance of embryos in related species converge in their appearance mid-way in development, diverging thereafter. But is this 'phylotypic stage' real, and how is it connected with the genetic basis of development? Here, a method linking the genes transcribed at various stages of development (the transcriptome) with the evolutionary history of those genes is used. Genes transcribed in the phylotypic stage are, in evolutionary terms, the oldest and most conserved. This suggests that the phylotypic stage does represent the body plans of related species at their most unadorned, selection having sculpted the earlier and later stages of embryonic form to suit the particulars of each creature.

In the retina, highly selective wiring from inhibitory cells contributes to determine the direction-selection characteristics of an individual ganglion cell, yet how the asymmetric wiring inherent to these connections is established was unknown. Here, two independent studies using complementary techniques, including pharmacology, electrophysiology and optogenetics, find that although inhibitory inputs to both sides of the direction-selective cell are uniform early in development, by the second postnatal week, inhibitory synapses on the null side strengthen whereas those on the preferred side remain constant. These plasticity changes occur independent of neural activity, indicating that a specific developmental program is executed to produce the direction-selective circuitry in the retina.

This study introduces a novel recording technique for simultaneously measuring excitatory and inhibitory conductances of retinal ganglion cells to show that excitatory and inhibitory inputs are strongly correlated, thereby cancelling each other. Furthermore, dynamic clamp is used to introduce these conductance changes into the cell with or without correlations, and it is found that, as predicted by theoretical work, correlations significantly increase reliability of the spiking response.

Here, a comprehensive study of the sodium/galactose transporter (vSGLT) is presented, consisting of molecular dynamics simulations, biochemical characterization and a new crystal structure of the 'inward-open' conformation. These experiments show that sodium exit causes a reorientation of transmembrane helix 1, opening an inner gate required for substrate exit, while also triggering minor rigid-body movements in two sets of transmembrane helical bundles. This cascade of conformational changes is responsible for the proper timing of ion and substrate release.

The positive relationship between biodiversity and ecosystem function is well established, but the specific shape of the relationship can vary. Here, experimental evolution is used to show that the strength and slope depends on evolutionary history, with specialists and generalists that have evolved from the same ancestor giving rise to different diversity–function relationships.