Next-generation sequencing has facilitated the study of how transposable elements and retroviruses select their diverse genomic sites of integration, and revealed integration site preferences that range from specific nucleotide sequences to particular chromatin states. The authors review the various mechanisms of integration site selection in eukaryotes, as well as the molecular and cellular determinants that guide this process.
The function of the genome crucially involves regulatory sequences, such as enhancers and promoters. Many questions remain unanswered as to how these regulatory elements work, and even identifying them can be a major challenge. New genomic technologies — including transcriptomics, genome sequencing and chromatin immunoprecipitation followed by sequencing — are enabling progress in this field. The articles in this series discuss recent views on regulatory elements, including their role in evolution and the function of chromatin modifications, as well as methods to study these important regions of the genome.
Transposable elements (TEs) are widely known for their deleterious consequences of selfish propagation and mutagenesis. However, as described in this Review, TEs also provide hosts with rich, beneficial gene-regulatory machinery in the form of regulatory DNA elements and TE-derived gene products. The authors highlight the diverse regulatory contributions of TEs to organismal physiology and pathology, provide a framework for responsibly assigning functional roles to TEs and offer visions for the future.
The observation that many, if not all, functional enhancers generate non-coding enhancer RNAs (eRNAs) has raised critical questions regarding the potential biological roles of the enhancer transcription process and, indeed, of eRNAs. This article reviews fundamental insights into the inter-regulation of enhancers and promoters and discusses unresolved questions regarding the functional role of enhancers as transcription units in genome regulation.
Gene-regulatory DNA elements control complex spatiotemporal patterns of gene expression, and alterations to these sequences are commonly associated with inter-individual phenotypic variation and human disease. This Review discusses our latest understanding of how different layers of information in these sequences control the binding of regulators and influence gene expression outcomes.
Enhancers are DNA elements that are key regulators of gene expression, but their complexities and context dependence makes their identification and characterization challenging. This Review discusses how an improved understanding of the varied properties of enhancers is being used in diverse approaches for the systematic prediction of enhancers genome wide.
Although enhancers are crucial and widespread gene-regulatory elements, we are far from a complete understanding of how they function or their importance in areas such as disease and evolution. Five prominent researchers discuss some of the key outstanding questions in enhancer biology.
Several approaches exist for identifying cis-regulatory modules, which are the regions in the genome that regulate gene expression. The authors describe these strategies and assess how they perform (either alone or in combination) and how they can be improved.
The improving functional annotation of genomes through the analysis of genome-wide data sets is revealing important characteristics of promoters. Similar classes of promoters are now emerging across diverse metazoan species, and novel features that contribute to gene regulation are being identified.
Changes in cis-regulatory sequences, especially enhancers, make a substantial contribution to phenotypic diversity among and within species. Recent studies have begun to uncover the mechanisms underlying cis-regulatory divergence, such as the types of mutations that occur and their influence on transcription factor binding.
Methodological advances have provided new insights into mechanisms of enhancer function, including the importance of specific chromatin modifications at enhancers for the establishment of gene expression programmes. Cohesin and non-coding RNAs are also emerging as key players in enhancer function.
The amount of genome-scale data on covalent histone modification patterns is rapidly increasing. This Review brings together current knowledge on how modification 'signatures' relate to the structure and function of chromatin, from regulatory elements and gene structure to organization in the nucleus.
Most of the human genome consists of non-protein-coding DNA. This article describes the progress made in annotating this non-coding portion of the genome by combining data from comparative and functional genomics analyses.
Increasing evidence suggests functional similarities between promoters and insulators. The authors propose that these findings unify existing models of insulator function, provide new directions for understanding how insulators work and suggest that insulators have evolved from promoters.