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Epigenome Roadmap

Welcome to the Epigenome Roadmap! Here, we have collected research papers describing the main findings of the NIH Roadmap Epigenomics Program, the aim of which was to systematically characterize epigenomic landscapes in primary human tissues and cells. The papers are complemented by eight threads each of which highlights a topic that runs through more than one paper. Threads are designed to help you explore the wealth of information collectively published across several Nature Research journals. Each thread consists of relevant paragraphs, figures and tables from across the papers, united around a specific theme.

We invite you to explore the research content, the News & Views, the video and other associated material.

 

News and Multimedia

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

Editorial | | Nature News

There is great interest in understanding the stages and transitions of cell development as pluripotent cells follow the neuronal lineage. Here, Alexander Meissner and colleagues characterize the transcriptional and epigenetic landscape of six consecutive stages as human embryonic stem cells differentiate along the neuronal lineage. The authors apply a powerful computational framework to the data and identify key regulators and their effects on the epigenetic remodelling during these consecutive stages of differentiation.

News & Views | | Nature

Nature Research Papers

As part of the Epigenome Roadmap project, Joseph Ecker and colleagues provide genome-wide maps of DNA methylation and transcriptomes, in conjunction with genomic DNA sequencing, of 18 different primary human tissue types from four individuals. Analysis of the datasets reveals widespread differential methylation of CG sites between tissues, and methylation at regulatory elements generally has a negative correlation with gene expression as expected. A surprising amount of non-CG methylation is found in a subpopulation of cells in many tissues.

Letter | Open Access | | Nature

Recent genome-wide association studies have shown substantial genetic variation in non-coding regions associated with Alzheimer's disease, suggesting the involvement of aberrant gene regulation. However, the functional significance of these variants remained unclear. By profiling transcriptional and chromatin state dynamics in a mouse model, Elizabeta Gjoneska and colleagues now show that the immune response genes and their regulatory regions are upregulated, whereas those involved in synaptic plasticity and learning and memory are downregulated. These changes are highly conserved between the mouse model and the human disease. Surprisingly, Alzheimer's disease-associated genetic variants are mainly enriched in higher-activity, immune-related enhancers, and are depleted in lower-activity, neural enhancers. This suggests that genetic predisposition to Alzheimer's may be primarily associated with immune functions, while neuronal plasticity may be affected primarily by non-genetic effects.

Letter | Open Access | | Nature

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.

Article | | Nature Communications

Hundreds of risk loci for autoimmunity have been identified previously in genome-wide association studies (GWASs), but the implicated loci comprise multiple variants in linkage disequilibrium and rarely alter protein-coding sequence, which complicates their interpretation. This study adopts a new approach for fine mapping causal genetic variants for 21 autoimmune diseases, applying a novel algorithm to GWAS-based loci and integrating genotypic data with epigenomic maps for specialized immune cells. The results implicate a very specific subset of enhancers involved in T-cell stimulation as causal determinants of autoimmune diseases.

Article | | Nature

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.

Article | Open Access | | Nature Communications

As part of the Epigenome Roadmap project, Bing Ren and colleagues use 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 tissues and between individuals. They authors investigate cis-regulatory relationships between genes and their control sequences and tissue-restricted activities of repetitive elements.

Letter | Open Access | | Nature

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.

Article | Open Access | | Nature Communications

The goal of the NIH Roadmap Epigenomics Consortium was to generate a reference collection of human epigenomes for primary cells and tissues. 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 show that disease and trait-associated genetic variants are enriched in predicted tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits and providing a resource for interpreting the molecular basis of human disease.

Article | Open Access | | Nature

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.

Article | | Nature Communications

There is great interest in understanding the stages and transitions of cell development as pluripotent cells follow the neuronal lineage. Here, Alexander Meissner and colleagues characterize the transcriptional and epigenetic landscape of six consecutive stages as human embryonic stem cells differentiate along the neuronal lineage. The authors apply a powerful computational framework to the data and identify key regulators and their effects on the epigenetic remodelling during these consecutive stages of differentiation.

Letter | | Nature

Higher-order chromatin structures are among the factors influencing gene expression, although how these structures evolve during differentiation and lineage specification in mammalian systems is still unclear. Bing Ren and colleagues have mapped the differences in genome-wide chromatin interactions between human embryonic stem cells and their differentiated progeny. They delineate biases in allelic gene expression that correlate with allele-biased chromatin interactions between distal enhancers and proximal promoters.

Article | Open Access | | Nature

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.

Article | Open Access | | Nature Communications

Genomic studies have shown that different cancer types vary substantially in the local density and types of somatic mutations. This has been explained not only by differences in DNA sequence but also by other features including epigenetic organization. Shamil Sunyaev and colleague now compare mutation densities to detailed epigenetic profiles of different cell types and tissues. They demonstrate that epigenomic features of a given cell type or tissue in which a cancer arises are much stronger determinants of mutational profiles than other properties. Conversely, the findings make it possible to deduce information on the possible tissue-of-origin of a tumour based on its mutational landscape.

Letter | Open Access | | Nature

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.

Article | | Nature Neuroscience

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.

Article | | Nature Communications

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.

Article | | Nature Neuroscience

Thread articles

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

Thread | | Nature

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

Thread | | Nature