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DNase I footprinting in 41 cell and tissue types reveals millions of short sequence elements encoding an expansive repertoire of conserved recognition sequences for DNA-binding proteins.

This study presents a large-scale enhancer screening approach to optimize gene therapy vectors. A compact, potent, erythroid-specific enhancer used in a therapeutic vector, improved viral titers, transducibility, and restored hemoglobin levels in β-thalassemia patient-derived cells.

A high-density DNase I cleavage map from 243 human cell and tissue types provides a genome-wide, nucleotide-resolution map of human transcription factor footprints.

The Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types; these data were compared with those from human to confirm substantial conservation in the newly annotated potential functional sequences and to reveal pronounced divergence of other sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization.

The authors present a statistical and computational framework to identify allele-specific variants, i.e., single nucleotide variants exhibiting allele-specificity (allelic imbalance) in any type of omics assay. Application of this framework to thousands of datasets yields an atlas of chromatin altering variants in diverse cell types.

Tiling of regulatory DNA with mutations introduced by genome editing nucleases and linking the resulting alleles to a phenotypic readout allows the precise determination of functional sequence motifs within these regions.

An extensive map of human DNase I hypersensitive sites, markers of regulatory DNA, in 125 diverse cell and tissue types is described; integration of this information with other ENCODE-generated data sets identifies new relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns.

This Perspective by Vierstra and Stamatoyannopoulos discusses the prospects and challenges of genomic footprinting applied to complex genomes.

By separately sequencing and mapping smaller and larger DNase I fragments from the same DNase I digestion experiment, the approach allows simultaneous profiling of transcription factor footprints relative to nucleosome occupancy.

Lineage differentiation and commitment is driven by transcription regulators and chromatin changes. Here the authors report daily profiling of chromatin accessibility and transcriptome changes during human erythropoiesis, relating these changes to lineage potential between erythropoiesis and megakaryopoieis.

High-resolution maps of DNase I hypersensitive sites from 733 human biosamples are used to identify and index regulatory DNA within the human genome.

Mouse genomic footprinting reveals conservation of transcription factor (TF) recognition repertoires and trans-regulatory circuitry despite massive turnover of DNA elements that contact TFs in vivo.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

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.

The genome of the wild grass Brachypodium distachyon (Brachypodium), a member of the Pooideae subfamily, is sequenced. The Pooideae are one of three subfamilies of grasses that provide the bulk of human nutrition and may become major sources of renewable energy. Availability of the genome sequence should help establish Brachypodium as a model for developing new energy and food crops.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

Matthew Maurano, John Stamatoyannopoulos and colleagues identify 64,597 allelically imbalanced SNPs that influence transcription factor occupancy in vivo. Using these data, they develop a general scoring method to identify regulatory variants likely to affect transcription factor occupancy in the human genome.

The authors summarize the history of the ENCODE Project, the achievements of ENCODE 1 and ENCODE 2, and how the new data generated and analysed in ENCODE 3 complement the previous phases.