Epigenome Roadmap

Studies of the epigenomic signatures of many healthy and diseased human tissues could provide crucial information to link genetic variation and disease.

A package of papers investigates the functional regulatory elements in genomes that have been obtained from human tissue samples and cell lines. The implications of the project are presented here from three viewpoints. See Articles p.317, p.331, p.337 & p.344 and Letters p.350, p.355, p.360 & p.365

A slew of papers reveals the chemical tweaks to DNA in a wealth of different cells — as explained with the help of a small orchestra.

As part of the Epigenome Roadmap Project, genome-wide maps of DNA methylation and transcriptomes together with genomic DNA sequencing of 18 different primary human tissue types from 4 individuals are presented; analysis reveals widespread differential methylation of CG sites between tissues, and the presence of non-CG methylation in adult tissues.

Analysis of transcriptional and epigenomic changes in the hippocampus of a mouse model of Alzheimer’s disease shows that immune function genes and regulatory regions are upregulated, whereas genes and regulatory regions involved in synaptic plasticity, learning and memory are downregulated; genetic variants associated with Alzheimer’s disease are only enriched in orthologues of upregulated immune regions, suggesting that dysregulation of immune processes may underlie Alzheimer’s disease predisposition.

There is epigenetic variability in the same cell type among healthy individuals, but the mechanism or significance of this variability is not clear. Here, the authors purify CD34+ cells from different individuals and use meta-epigenomic approaches to analyse and explain the epigenetic variability observed.

Genome-wide association studies combined with data from epigenomic maps for immune cells have been used to fine-map causal variants for 21 autoimmune diseases; disease risk tends to be linked to single nucleotide polymorphisms in cell-type-specific enhancers, often in regions adjacent to transcription factor binding motifs.

Tissue-specific functions have been established for some lincRNAs. Here, by analysing 111 reference epigenomes from the NIH Roadmap Epigenomics project, the authors report tissue-specific epigenomic regulation of 3,753 lincRNAs and their strong connection with tissue-specific pathways.

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.

Large-scale epigenomic profiles are predicted from experimental data using multiple regression tree models.

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.

As part of the Epigenome Roadmap project, this study uses a chromosome-spanning haplotype reconstruction strategy to construct haplotype-resolved epigenomic maps for a diverse set of human tissues; the maps reveal extensive allelic biases in chromatin state and transcription, which vary across individuals due to genetic backgrounds.

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.

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.

The functional relevance of age-related variation in DNA methylation is unclear. Here, Reynolds et al. analyze how patterns of genome-wide gene expression and DNA methylation data vary with age in circulating monocytes and T cells, and report age-associated methylation signals that are correlated with cis-gene expression and vascular aging.

The integrative analysis of epigenetic footprints along consecutive stages of neural progenitors derived from human ES cells reveals regulatory mechanisms that orchestrate stage-specific differentiation.

The analysis pipeline Epigram finds DNA motifs predictive of histone modifications and regions that lack DNA methylation.

An analysis of genome-wide chromatin interactions during human embryonic stem cell differentiation reveals changes in chromatic organization and simultaneously identifies allele-resolved chromatin structure and differences in gene expression during differentiation.

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.

An analysis of cell-type-specific epigenomic features reveals a relationship between epigenomic and mutational profiles; chromatin characteristics can explain a large proportion of mutational variance in cancer genomes and the mutational distribution can identify the probable cell type from which a given cancer originated from.

Aging can lead to cognitive decline associated with neural pathology and Alzheimer's disease (AD). Here the authors scan the methylation status of CpGs across the entire genome of brain samples from aged subjects in an epigenome-wide association study (EWAS). Several loci, including ANK1, were associated with AD pathology, gene expression and AD genetic risk networks.

Genome-wide epigenetic analyses can yield new insights into disease pathways. Vijayanand and colleagues mapped transcriptional enhancers in human T cells from healthy and asthmatic individuals and identify asthma-specific T_H2 cell–associated enhancers.

Extreme fetal growth is associated with increased risk of various adult diseases, although the mechanism underlying these associations is poorly understood. Here the authors show that abnormal fetal growth correlates with increased DNA methylation levels and report sex-specific epigenetic patterns associated with fetal growth.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive neuropathology and cognitive decline. Here the authors describe an epigenome-wide association study (EWAS) of human post-mortem brain samples across multiple independent AD cohorts. They find consistent hypermethylation of the ANK1 gene associated with neuropathology.

Reference epigenomes enable comprehensive annotations of dynamic non-coding regulatory and transcribed elements across hundreds of human cell types and tissues

Integrative analyses of reference epigenomes reveal complex context-specific relationships between chromatin state, accessibility, DNA methylation and gene expression

Reference epigenomes reveal relationships between cell types and tissues, and the regulatory mechanisms underlying differentiation and development

Integrative analyses of reference epigenomes reveal context-specific regulatory motifs, factors, modules, pathways and networks

Reference epigenomes provide leads about the cell-type specificity and molecular basis of natural and disease-associated genetic variants

Epigenome profiling reveals multi-tissue regulatory dynamics associated with progression of cancer, Alzheimer’s disease and other complex diseases

Reference epigenomes spanning multiple fetal and adult brain regions provide new insights into brain development and neurodegenerative disorders

Robust statistical pipelines and novel computational methods enable large-scale integrative analysis of reference epigenomes