Volume 518 Number 7540

Editorials

When right beats might p.455

The final act in a long-running Italian saga should bring tighter controls on unproven stem-cell therapies, both at home and abroad.

doi: 10.1038/518455a

No strings p.456

Details of a climate-change sceptic’s links to the energy industry make worrying reading.

doi: 10.1038/518456a

A sore thing p.456

The use of technologies that objectively measure pain must be carefully monitored.

doi: 10.1038/518456b

News

News Features

The Pluto siblings p.470

Leslie and Eliot Young have spent their lives studying Pluto. Now they are gearing up for the biggest event of their careers.

doi: 10.1038/518470a

The painful truth p.474

Brain-scanning techniques promise to give an objective measure of whether someone is in pain, but researchers question whether they are reliable enough for the courtroom.

doi: 10.1038/518474a

News & Views

Learning to see and act p.486

An artificial-intelligence system uses machine learning from massive training sets to teach itself to play 49 classic computer games, demonstrating that it can adapt to a variety of tasks. See Letter p.529

doi: 10.1038/518486a

The benefits of traditional knowledge p.487

A study of two Balkan ethnic groups living in close proximity finds that traditional knowledge about local plant resources helps communities to cope with periods of famine, and can promote the conservation of biodiversity.

doi: 10.1038/518487a

Chasing blood p.488

Many experiments have probed the mechanisms by which transplanted stem cells give rise to all the cell types of the blood, but it emerges that the process is different in unperturbed conditions. See Letter p.542

doi: 10.1038/nature14203

A giant in the young Universe p.490

Astronomers have discovered an extremely massive black hole from a time when the Universe was less than 900 million years old. The result provides insight into the growth of black holes and galaxies in the young Universe. See Letter p.512

doi: 10.1038/518490b

Teleportation for two p.491

The 'no-cloning' theorem of quantum mechanics forbids the perfect copying of properties of photons or electrons. But quantum teleportation allows their flawless transfer — now even for two properties simultaneously. See Letter p.516

doi: 10.1038/518491a

RNA modification does a regulatory two-step p.492

The m6A structural modification of RNA regulates gene expression. It has now been found to mediate an unusual control mechanism: by altering the structure of RNA, m6A allows a regulatory protein to bind to that RNA. See Letter p.560

doi: 10.1038/518492a

Articles

Whole genomes redefine the mutational landscape of pancreatic cancer p.495

A whole-genome sequencing analysis of 100 pancreatic ductal adenocarcinomas has discovered known and newly identified genetic drivers of pancreatic cancer; these genetic alterations can be classified into four subtypes, which raises the possibility of improved targeting of clinical treatments.

doi: 10.1038/nature14169

Lagging-strand replication shapes the mutational landscape of the genome p.502

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.

doi: 10.1038/nature14183

Crystal structure of the V(D)J recombinase RAG1–RAG2 p.507

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.

doi: 10.1038/nature14174

Letters

Quantum teleportation of multiple degrees of freedom of a single photon p.516

The quantum teleportation of composite quantum states of a single photon encoded in both spin and orbital angular momentum is achieved, with a teleportation fidelity above the classical limit, by quantum non-demolition measurement assisted discrimination of the Bell states describing the entanglement of the two degrees of freedom.

doi: 10.1038/nature14246

Dynamically reconfigurable complex emulsions via tunable interfacial tensions p.520

The temperature-sensitive miscibility of hydrocarbon, silicone and fluorocarbon liquids is used to establish a one-step method of making three- and four-phase complex emulsions with highly controllable morphologies that can be alternated between encapsulated and Janus configurations by varying the balance of interfacial tensions.

doi: 10.1038/nature14168

An extremely high-altitude plume seen at Mars’ morning terminator p.525

Examination of amateur observations of Mars shows atmospheric plumes 200 to 250 kilometres high that are observed in the morning but not in the evening over a period of more than a week; our current understanding of Martian atmospheric dynamics and plume formation cannot account for the creation of such enormous plumes.

doi: 10.1038/nature14162

Human-level control through deep reinforcement learning p.529

An artificial agent is developed that learns to play a diverse range of classic Atari 2600 computer games directly from sensory experience, achieving a performance comparable to that of an expert human player; this work paves the way to building general-purpose learning algorithms that bridge the divide between perception and action.

doi: 10.1038/nature14236

Fundamental properties of unperturbed haematopoiesis from stem cells in vivo p.542

Inducible genetic labelling of haematopoietic stem cells (HSCs) and linked mathematical modelling show that at least 30% of all HSCs are productive, and that adult haematopoiesis is largely sustained by ‘short-term’ downstream stem cells that operate near self-renewal in the steady state; HSC fate mapping provides a quantitative model for better understanding of HSC functions in health and disease.

doi: 10.1038/nature14242

Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia p.552

Somatic TP53 mutations are highly prevalent in therapy-related acute myeloid leukaemia and myelodysplastic syndrome, which arise as complications of cytotoxic chemotherapy or radiotherapy; although it was believed that these TP53 mutations are directly induced by cytotoxic therapy, new data indicate that they predate cytotoxic therapy and that haematopoietic progenitors harbouring these pre-existing mutations may selectively expand after exposure to chemotherapy or radiotherapy.

doi: 10.1038/nature13968

Enhancer–core-promoter specificity separates developmental and housekeeping gene regulation p.556

Gene transcription in animals involves the assembly of RNA polymerase II at core promoters and its cell-type-specific activation by enhancers that can be located more distally. However, how ubiquitous expression of housekeeping genes is achieved has been less clear. In particular, it is unknown whether ubiquitously active enhancers exist and how developmental and housekeeping gene regulation is separated. An attractive hypothesis is that different core promoters might exhibit an intrinsic specificity to certain enhancers. This is conceivable, as various core promoter sequence elements are differentially distributed between genes of different functions, including elements that are predominantly found at either developmentally regulated or at housekeeping genes. Here we show that thousands of enhancers in Drosophila melanogaster S2 and ovarian somatic cells (OSCs) exhibit a marked specificity to one of two core promoters—one derived from a ubiquitously expressed ribosomal protein gene and another from a developmentally regulated transcription factor—and confirm the existence of these two classes for five additional core promoters from genes with diverse functions. Housekeeping enhancers are active across the two cell types, while developmental enhancers exhibit strong cell-type specificity. Both enhancer classes differ in their genomic distribution, the functions of neighbouring genes, and the core promoter elements of these neighbouring genes. In addition, we identify two transcription factors—Dref and Trl—that bind and activate housekeeping versus developmental enhancers, respectively. Our results provide evidence for a sequence-encoded enhancer–core-promoter specificity that separates developmental and housekeeping gene regulatory programs for thousands of enhancers and their target genes across the entire genome.

doi: 10.1038/nature13994

N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions p.560

RNA-binding proteins control many aspects of cellular biology through binding single-stranded RNA binding motifs (RBMs). However, RBMs can be buried within their local RNA structures, thus inhibiting RNA–protein interactions. N6-methyladenosine (m6A), the most abundant and dynamic internal modification in eukaryotic messenger RNA, can be selectively recognized by the YTHDF2 protein to affect the stability of cytoplasmic mRNAs, but how m6A achieves its wide-ranging physiological role needs further exploration. Here we show in human cells that m6A controls the RNA-structure-dependent accessibility of RBMs to affect RNA–protein interactions for biological regulation; we term this mechanism ‘the m6A-switch’. We found that m6A alters the local structure in mRNA and long non-coding RNA (lncRNA) to facilitate binding of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an abundant nuclear RNA-binding protein responsible for pre-mRNA processing. Combining photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) and anti-m6A immunoprecipitation (MeRIP) approaches enabled us to identify 39,060 m6A-switches among HNRNPC-binding sites; and global m6A reduction decreased HNRNPC binding at 2,798 high-confidence m6A-switches. We determined that these m6A-switch-regulated HNRNPC-binding activities affect the abundance as well as alternative splicing of target mRNAs, demonstrating the regulatory role of m6A-switches on gene expression and RNA maturation. Our results illustrate how RNA-binding proteins gain regulated access to their RBMs through m6A-dependent RNA structural remodelling, and provide a new direction for investigating RNA-modification-coded cellular biology.

doi: 10.1038/nature14234