A large number of cis-regulatory sequences have been annotated in the human genome1,2, but defining their target genes remains a challenge3. One strategy is to identify the long-range looping interactions at these elements with the use of chromosome conformation capture (3C) based techniques4. However, previous studies lack either the resolution or coverage to permit a whole-genome, unbiased view of chromatin interactions. Here, we report a comprehensive chromatin interaction map generated in human fibroblasts using a genome-wide 3C analysis method (Hi-C)5. We determined over one million long-range chromatin interactions at 5–10kb resolution, and uncovered general principles of chromatin organization at different types of genomic features. We also characterized the dynamics of promoter-enhancer contacts upon TNF-α signaling in these cells. Unexpectedly, we found that TNF-α responsive enhancers are already in contact with their target promoters prior to signaling. Such pre-existing chromatin looping, which also exists in other cell types with different extra-cellular signaling, is a strong predictor of gene induction. Our observations suggest that the three-dimensional chromatin landscape, once established in a particular cell type, is rather stable and could influence the selection or activation of target genes by a ubiquitous transcription activator in a cell-specific manner.

SUMMARY Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To investigate epigenetic regulation of embryonic development, we differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast-like cells, and mesenchymal stem cells, and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage. We found that promoters that are active in early developmental stages tend to be CG rich and mainly engage H3K27me3 upon silencing in non-expressing lineages. By contrast, promoters for genes expressed preferentially at later stages are often CG poor and primarily employ DNA methylation upon repression. Interestingly, the early developmental regulatory genes are often located in large genomic domains that are generally devoid of DNA methylation in most lineages, which we termed DNA methylation valleys (DMVs). Our results suggest that distinct epigenetic mechanisms regulate early and late stages of ES cell differentiation.

Summary In mammals, cytosine methylation (5mC) is widely distributed throughout the genome, but is notably depleted from active promoters and enhancers. While the role of DNA methylation in promoter silencing has been well documented, the function of this epigenetic mark at enhancers remains unclear. Recent experiments have demonstrated that enhancers are enriched for 5-hydroxymethylcytosine (5hmC), an oxidization product of the Tet family of 5mC dioxygenases and an intermediate of DNA demethylation. These results support the involvement of Tet proteins in regulation of dynamic DNA methylation at enhancers. By mapping DNA methylation and hydroxymethylation at base resolution, we find that deletion of Tet2 causes extensive loss of 5hmC at enhancers, accompanied by enhancer hypermethylation, reduction of enhancer activity, and delayed gene induction in the early steps of differentiation. Our results reveal that DNA demethylation modulates enhancer activity, and its disruption influences the timing of transcriptome reprogramming during cellular differentiation.

Allelic differences between the two homologous chromosomes can affect the propensity of inheritance in humans; however, the extent of such differences in the human genome has yet to be fully explored. Here, for the first time, we delineate allelic chromatin modifications and transcriptomes amongst a broad set of human tissues, enabled by a chromosome-spanning haplotype reconstruction strategy1. The resulting masses of haplotype-resolved epigenomic maps reveal extensive allelic biases in both chromatin state and transcription, which show considerable variation across tissues and between individuals, and allow us to investigate cis-regulatory relationships between genes and their control sequences. Analyses of histone modification maps also uncover intriguing characteristics of cis-regulatory elements and tissue-restricted activities of repetitive elements. The rich datasets described here will enhance our understanding of the mechanisms of how cis-regulatory elements control gene expression programs.

Diet is the most variable aspect of life history, as most individuals have a large diversity of food choices, varying in the type and amount that they ingest. In the short-term, diet can affect metabolism and energy levels. However, in the long run, the net deficiency or excess of calories from diet can influence the progression and severity of age-related diseases. An old and yet still debated question is: how do specific dietary choices impact health- and lifespan? It is clear that genetics can play a critical role — perhaps just as important as diet choices. For example, poor diet in combination with genetic susceptibility can lead to metabolic disorders, such as obesity and type 2 diabetes. Recent work in Caenorhabditis elegans has identified the existence of diet-gene pairs, where the consequence of mutating a specific gene is only realized on specific diets. Many core metabolic pathways are conserved from worm to human. Although only a handful of these diet-gene pairs has been characterized, there are potentially hundreds, if not thousands, of such interactions, which may explain the variability in the rates of aging in humans and the incidence and severity of age-related diseases.