The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in 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. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

): Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure–related phenotypes. We identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn’s disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.

Systematic Localization of Common Disease-Associated Variation in

The advent of new technologies and analytic approaches is beginning to provide an unprecedented look at features of the human genome that affect RNA expression. These “epigenomic” features are found in a number of different forms: they include DNA methylation, covalent modifications of histone proteins and non-coding RNAs. Some of these features have now been implicated in Alzheimer’s disease (AD). Here, we focus on recent studies that have identified robust observations relating to DNA methylation and chromatin in human brain tissue; these findings will ground the next generation of studies and provide a model for the design of such studies. Stemming from observations that compounds with histone deacetylase activity may be beneficial in AD, epigenome-wide studies in cortical samples from large numbers of human subjects have now shown that AD-associated epigenomic changes are reproducible, are not driven by genetic risk factors, and are widespread at specific locations in the genome. A fundamental question of whether such changes are causal remains to be demonstrated, but it is already clear that well-powered investigations of the human epigenome in the target organ of a neurodegenerative disease are feasible, are implicating new areas of the genome in the disease, and will be an important tool for future studies. We are now at an inflection point: as genome-wide association studies of genetic variants come to an end, a new generation of studies exploring the epigenome will provide an important new layer of information with which to enrich our understanding of AD pathogenesis and to possibly guide development of new therapeutic targets.

/pdf/the-epigenome-in-alzheimer-s-disease-current-state-and-3563plrd2e.pdf

The epigenome in Alzheimer’s disease: current state and approaches for a new path to gene discovery and understanding disease mechanism

This paper identifies and discusses the benefits, threats, and vulnerabilities related to the digital revolution. It aims to motivate research and its funding regarding digital threats and vulnerabilities related, in particular, to anticipating unintended, undesirable rebound effects, tipping points, critically fast evolutionary change rates, trade-offs, etc. A brief analysis of the history of the mind and technology reveals slow technological development over tens of thousands of years (including the invention of a place-value digital number system). Then, a small series of groundbreaking ideas (e.g., binary logic, Shannon’s symbolic analysis of relay and switching circuits, architectures of computing) enabled the industry-driven invention of programmable computing machines. Ultimately, the mastery of electron and semiconductor physics allowed for economical and seemingly unlimited storage capacity that made digital tools available to all domains of society. Based on the historical analysis, a coupled human-environment systems perspective (that includes a hierarchy assumption ranging from the human cell to the human species) enables the identification of several potential challenges to society and science. First, digital nano-engineering promotes genetic modifications (i.e., directed evolution), and synthetic biology enables a new level of the appropriation of nature. The understanding of cell-based biocomputers may call for new forms of logic. These and other challenges require thorough sustainability research in order to anticipate major changes on all levels of human systems. Second, the human individual is exposed to new forms of vulnerability. In particular, the potential epigenetic effects resulting from the excessive use of digital information of historically unknown speed, density, and contents and the loss of (the Western common-law right to) privacy resulting from big data (whose ownership is often unknown) should become subjects of research. Third, digital technologies are responsible for rapid changes in all social and economic structures. The paper suggests that thorough, discipline-based interdisciplinary research is needed in order to develop basic knowledge for creating and managing resilient relationships between human systems and their digital environments.

/pdf/sustainable-digital-environments-what-major-challenges-is-49u4c80kwf.pdf

Sustainable Digital Environments: What Major Challenges Is Humankind Facing?

The NIH Roadmap Epigenomics Program was launched to deliver reference epigenomic data from human tissues and cells, develop tools and methods for analyzing the epigenome, discover novel epigenetic marks, develop methods to manipulate the epigenome, and determine epigenetic contributions to diverse human diseases. Here, we comment on the outcomes from this program: the scientific contributions made possible by a consortium approach and the challenges, benefits, and lessons learned from this group science effort.

https://advances.sciencemag.org/content/advances/5/7/eaaw6507.full.pdf

The NIH Common Fund/Roadmap Epigenomics Program: Successes of a comprehensive consortium

This chapter describes resources and technologies generated by the NIH Roadmap Epigenomics Program that may be useful to epigenomics researchers investigating a variety of diseases including cancer. Highlights include reference epigenome maps for a wide variety of human cells and tissues, the development of new technologies for epigenetic assays and imaging, the identification of novel epigenetic modifications, and an improved understanding of the role of epigenetic processes in a diversity of human diseases. We also discuss future needs in this area including exploration of epigenomic variation between individuals, single-cell epigenomics, environmental epigenomics, exploration of the use of surrogate tissues, and improved technologies for epigenome manipulation.

Kim McAllister

Papers

The NIH Common Fund/Roadmap Epigenomics Program: Successes of a comprehensive consortium

Community Resources and Technologies Developed Through the NIH Roadmap Epigenomics Program