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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.

Genome-wide maps of transcription factor binding are prompting the re-examination of traditional concepts of transcriptional regulation. Current challenges centre on understanding which binding events are functional, how transcription factors cooperate and how to integrate the genomic and chromatin context into models of gene regulation.

In prostate cancer, chromatin structure can impact the transcriptome. Here, the authors develop high resolution chromatin interaction maps in prostate cancer cells using in situ Hi-C, revealing prostate cancer-specific TADs and enhancer-promoter loops surrounding the androgen receptor (AR) locus.

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.

Renewable affinity reagents with high specificity and affinity for histone modifications perform well in ChIP-seq and other applications in epigenetics research.

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.

A description is given of the ENCODE consortium’s efforts to examine the principles of human transcriptional regulatory networks; the results are integrated with other genomic information to form a hierarchical meta-network where different levels have distinct properties.

Previous studies identified genetic variants associated with colorectal cancer (CRC), but the functional consequences of these genetic risk factors remain poorly understood. Here, the authors report that CRC risk variants reside in promoters and enhancers and could increase colon cancer risk through gene expression regulation.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

Epigenetic changes associated with post-natal differentiation have been characterized. Here the authors generate epigenomic and transcriptional profiles from primary human breast cells, providing insights into the transcriptional and epigenetic events that define post-natal cell differentiation in vivo.

Epigenomes are thought to retain molecular memories of their developmental history. Here, by comparing differentially methylated regions of genomes from different cells, the authors reveal an epigenetic signature that underlies a shared gene regulatory network with a common developmental origin.

Many loci in the mammalian genome are intermediately methylated. Here, by comprehensively identifying these loci and quantifying their relationship with gene activity, the authors show that intermediate methylation is an evolutionarily conserved epigenomic signature of gene regulation.

The transcription factor Ikaros, which is essential for lymphocyte development, contains multiple zinc fingers. Smale and colleagues show that mice lacking different zinc fingers develop distinct lymphocyte-developmental defects and tumor susceptibility.

The cellular heterogeneity in brain obscures the identification of robust cellular regulatory networks. Here the authors integrate genome-wide chromosome conformation data from sorted neurons and glia, with transcriptomic and enhancer profiles, to characterize cell-type-specific gene regulatory landscapes in the human brain, and provide insights into cell-type-specific gene regulatory networks in brain disorders.

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.

The NIH Roadmap Epigenomics Mapping Consortium aims to produce a public resource of epigenomic maps for stem cells and primary ex vivo tissues selected to represent the normal counterparts of tissues and organ systems frequently involved in human disease.

Ting Wang, Joseph Costello and colleagues report DNA methylation profiles of 11 human tissue types and show that DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer activity.

Methods for profiling DNA methylation differ in the physical principles used to detect modified cytosines. Harris et al. compare the performances of four sequencing-based technologies for genome-wide analysis of DNA methylation and combine two methods to enable detection of allelic differences in epigenetic marks.

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.

Recent research on disparate psychiatric disorders has implicated rare variants in genes involved in global gene regulation and chromatin modification, as well as many common variants located primarily in regulatory regions of the genome. Understanding precisely how these variants contribute to disease will require a deeper appreciation for the mechanisms of gene regulation in the developing and adult human brain. The PsychENCODE project aims to produce a public resource of multidimensional genomic data using tissue- and cell type–specific samples from approximately 1,000 phenotypically well-characterized, high-quality healthy and disease-affected human post-mortem brains, as well as functionally characterize disease-associated regulatory elements and variants in model systems. We are beginning with a focus on autism spectrum disorder, bipolar disorder and schizophrenia, and expect that this knowledge will apply to a wide variety of psychiatric disorders. This paper outlines the motivation and design of PsychENCODE.

There has been a tendency to associate the development of distinct CD4⁺T cell subsets with the expression of 'master regulator' transcription factors. Here, the authors discuss the shortcomings of this model and explain why 'lineage-specifying' may be a more fitting way to describe these key transcription factors.