Volume 489 Number 7414



News Features

News & Views

Materials scienceA hard concept in soft matter p.36

Hydrogels have many potential applications, but their mechanical strength is low. By simultaneously crosslinking two kinds of polymers in different ways, a highly fracture-resistant hydrogel has been made. See Letter p.133

doi: 10.1038/489036a

CosmologyThe lithium problem p.37

The theory that predicts how the lightest elements formed after the Big Bang has hitherto failed to explain the amount of cosmic lithium. The detection of interstellar lithium beyond the Milky Way gives this theory a boost. See Article p.121

doi: 10.1038/489037a

NeuroscienceLessons from heartbreak p.38

Male fruitflies quickly learn that courting already-mated females is useless. It turns out that a small subset of neurons in the male brain signals this negative experience and controls pheromone sensitivity. See Letter p.145

doi: 10.1038/489038a

Climate changeBrief but warm Antarctic summer p.39

A temperature record derived from measurements of an ice core drilled on James Ross Island, Antarctica, prompts a rethink of what has triggered the recent warming trends on the Antarctic Peninsula. See Letter p.141

doi: 10.1038/nature11483

Surface scienceSeparation by reconfiguration p.41

Membranes have been made that are hygro-responsive — their wetting properties change when immersed in water. This striking property allows the membrane to separate emulsions into their oil and water constituents.

doi: 10.1038/489041a

AstronomyOutflows from the first quasars p.42

Black holes are best known for pulling matter in. But a distant supermassive black hole, observed as it was when the Universe was less than a billion years old, has been seen pushing gas out of its host galaxy.

doi: 10.1038/489042a

Structural biologyA protein engagement RING p.43

The mechanistic details of the attachment of a small protein, ubiquitin, to other proteins are unclear. Crystal structures of the complexes formed by the E2–ubiquitin and RING E3 enzymes offer new insights. See Article p.115

doi: 10.1038/489043a

GenomicsENCODE explained p.52

The Encyclopedia of DNA Elements (ENCODE) project dishes up a hearty banquet of data that illuminate the roles of the functional elements of the human genome. Here, six scientists describe the project and discuss how the data are influencing research directions across many fields. See Articles p.57, p.75, p.83, p.91, p.101 & Letter p.109

doi: 10.1038/489052a

News & Views Forum


The accessible chromatin landscape of the human genome p.75

DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ∼2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ∼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.

doi: 10.1038/nature11232

An expansive human regulatory lexicon encoded in transcription factor footprints p.83

Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human cis–regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNase I cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of protein–DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50-base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation and pluripotency.

doi: 10.1038/nature11212

Architecture of the human regulatory network derived from ENCODE data p.91

Transcription factors bind in a combinatorial fashion to specify the on-and-off states of genes; the ensemble of these binding events forms a regulatory network, constituting the wiring diagram for a cell. To examine the principles of the human transcriptional regulatory network, we determined the genomic binding information of 119 transcription-related factors in over 450 distinct experiments. We found the combinatorial, co-association of transcription factors to be highly context specific: distinct combinations of factors bind at specific genomic locations. In particular, there are significant differences in the binding proximal and distal to genes. We organized all the transcription factor binding into a hierarchy and integrated it with other genomic information (for example, microRNA regulation), forming a dense meta-network. Factors at different levels have different properties; for instance, top-level transcription factors more strongly influence expression and middle-level ones co-regulate targets to mitigate information-flow bottlenecks. Moreover, these co-regulations give rise to many enriched network motifs (for example, noise-buffering feed-forward loops). Finally, more connected network components are under stronger selection and exhibit a greater degree of allele-specific activity (that is, differential binding to the two parental alleles). The regulatory information obtained in this study will be crucial for interpreting personal genome sequences and understanding basic principles of human biology and disease.

doi: 10.1038/nature11245

Landscape of transcription in human cells p.101

Eukaryotic cells make many types of primary and processed RNAs that are found either in specific subcellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available and their characteristic subcellular localizations are also poorly understood. Because RNA represents the direct output of the genetic information encoded by genomes and a significant proportion of a cell’s regulatory capabilities are focused on its synthesis, processing, transport, modification and translation, the generation of such a catalogue is crucial for understanding genome function. Here we report evidence that three-quarters of the human genome is capable of being transcribed, as well as observations about the range and levels of expression, localization, processing fates, regulatory regions and modifications of almost all currently annotated and thousands of previously unannotated RNAs. These observations, taken together, prompt a redefinition of the concept of a gene.

doi: 10.1038/nature11233



Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis p.115

Ubiquitin modification is mediated by a large family of specificity determining ubiquitin E3 ligases. To facilitate ubiquitin transfer, RING E3 ligases bind both substrate and a ubiquitin E2 conjugating enzyme linked to ubiquitin via a thioester bond, but the mechanism of transfer has remained elusive. Here we report the crystal structure of the dimeric RING domain of rat RNF4 in complex with E2 (UbcH5A) linked by an isopeptide bond to ubiquitin. While the E2 contacts a single protomer of the RING, ubiquitin is folded back onto the E2 by contacts from both RING protomers. The carboxy-terminal tail of ubiquitin is locked into an active site groove on the E2 by an intricate network of interactions, resulting in changes at the E2 active site. This arrangement is primed for catalysis as it can deprotonate the incoming substrate lysine residue and stabilize the consequent tetrahedral transition-state intermediate.

doi: 10.1038/nature11376