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The next step after sequencing a genome is to figure out how the cell actually uses it as an instruction manual. A large international consortium has examined 1% of the genome for what part is transcribed, where proteins are bound, what the chromatin structure looks like, and how the sequence compares to that of other organisms.

In the course of characterizing short RNAs from human cells using single-molecule high-throughput sequencing, these authors identify a new short RNA species. The presence of non-genomically encoded poly(U) residues at their 5' ends implies the existence of an unknown RNA copying mechanism in human cells.

The transcriptomes of eukaryotic cells are unexpectedly complex, with virtually the entire non-repeat portions of many genomes being transcribed. Using deep sequencing, this study reveals that a remarkable breadth of RNA species that come from both within annotated genes and from unannotated intergenic regions in human cells. Many of these small RNAs possess cap structures and seem to be processed from mature mRNAs resulting in populations of long and short RNAs with capped 5' ends that coincide.

A description is given of the ENCODE effort to provide a complete catalogue of primary and processed RNAs found either in specific subcellular compartments or throughout the cell, revealing that three-quarters of the human genome can be transcribed, and providing a wealth of information on the range and levels of expression, localization, processing fates and modifications of known and previously unannotated RNAs.

Abasic (AP) sites represent a prominent type of DNA damage, yet the genomics of this lesion remains unexplored. Here, the authors report a method to map such sites at the nucleotide level in complex genomes and use it to extract complex age- and tissue-dependent patterns of AP sites in mammals.

A genome-wide screen discovers a naturally occurring ribozyme in humans termed hovlinc, which is embedded within a long noncoding RNA and has no apparent relation to known ribozymes.

Single strand breaks represent the most common form of DNA damage yet no methods to map them in a genome-wide fashion at single nucleotide resolution exist. Here the authors develop such a method and apply to uncover patterns of single-strand DNA “breakome” in different biological conditions.

Senescence is associated with chromatin reorganization in heterochromatin foci. Here the authors show that VAD, a very long intergenic non-coding RNA activated by senescence, inhibits the incorporation of the repressive histone variant H2A.Z to INK4promoters in senescent cells.

The Hoppel transposable element mediates heterochromatin formation in Drosophila. Here Savva et al. report that the RNA-editing enzyme, ADAR, edits a long double-stranded RNA generated by the Hoppeltransposon, thereby regulating heterochromatin formation and gene expression.

Capturing the 5′ end of transcripts from an input of only 1,000 cells and linking the transcription start sites to downstream sequences allows the analysis of complex transcriptome architecture.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

Genome-wide analyses of transcriptional output in eukaryotes have revealed an unanticipated transcriptome complexity. These findings imply a complex, interleaved genomic organization, in which individual sequences carry multiple and overlapping informational content. The authors discuss the evidence for, and functional and evolutionary consequences of, this organization.

The 5-hydroxymethylcytosine (5-hmC) nucleoside is abundant in the brain for unknown reasons. Genome-wide analysis of the distribution of 5-hmC versus 5-methylcytosine (5-mC) in human and mouse tissues now shows that 5-hmC is enriched in genes with synaptic functions. The differential distribution of 5-hmC versus 5-mC at exon-intron boundaries in both human and mouse tissues further suggests a possible role for 5-hmC in pre-mRNA splicing.

This Consensus Statement addresses the definition, nomenclature and classification of long non-coding RNAs, and provides a shared viewpoint on their features and functions. The authors also discuss research challenges and provide recommendations to advance our understanding of long non-coding RNAs.

The accurate and thorough genome-wide detection of A-to-I editing has proven technically challenging. Using a combination of computational prediction and experimental validation, the authors report ~3,500 high-probability editing sites with sufficient accuracy to reveal the global patterns underlying biological functions of RNA editing in adult male Drosophila melanogaster.