United States of America
NIH Roadmap Epigenomics Program
The NIH Roadmap Epigenomics Program began in 2008. Under the umbrella of this program, the NIH Common Fund and NIH Institutes and Centers have supported a total of 68 grants in the areas of epigenetic technology development, identification of novel epigenetic marks, reference epigenome mapping, and disease epigenomics investigations. Details concerning the funded projects, resources, protocols generated, and scientific publications (around 200 to date) can be found at https://commonfund.nih.gov/epigenomics/.
Mapping the human genome: A community resource
Epigenetic modifications are chemical modifications to the genome that play a role in development, aging, health, and disease, and are therefore targets for therapeutic interventions. The Reference Epigenomic Mapping Consortium, funded through the Common Fund’s Roadmap Epigenomics Program, is generating genome-wide epigenomic maps for a variety of cell and tissue types.
The majority of the reference epigenomes generated will contain information on epigenetic modifications including a core set of histone marks, DNA methylation, chromatin accessibility, and gene expression information. A subset of reference epigenomes will also contain an expanded set of at least twenty additional histone modifications. For a description of the NIH Roadmap Epigenomics Program mapping efforts please refer to The NIH Roadmap Epigenomics Mapping Consortium. Bernstein et al. Nat Biotechnol, 2010. 28(10):1045-1048.
Data for 52 complete epigenomes and many partial datasets for a diversity of “normal” human cells and tissues are currently available http://www.roadmapepigenomics.org/. Some of the cells and tissues mapped thus far include embryonic stem (ES) cells, ES-cell derivatives, induced pluripotent stem cells, multiple fetal tissues, several varieties of blood and immune cells, breast cell types, placenta, and solid tissues (e.g. adipose, gastrointestinal tract, skin, and brain). There are plans to complete 50-100 additional epigenomes by the end of the program. Assay protocols and recommended data standards are also available.
Analysis of this data will help us predict functional genomic elements, understand cross-talk between epigenetic regulatory mechanisms, understand cellular programming and reprogramming, and provide baseline information to help human disease researchers.
Additional mapping center discoveries or publications
- Development of the protocol and completion of the first human methylome datasets. Lister, R., et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature, 2009. 462(7271):315-322.
- Development of a base resolution assay enabling genomewide characterization of hydroxymethylation (hmC). hmC is enriched in embryonic stem cells and some types of neurons. hmC functions still not clear. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Yu et al. Cell. 2012 Jun 8;149(6):1368-80.
- New protocol allowing whole genome profiling from 10,000 cells using nano-ChIP-seq, resulting in a 2-3 fold order of magnitude improvement in sensitivity. Whole-genome chromatin profiling from limited numbers of cells using nano-ChIP-seq. Adli and Bernstein. Nat Protoc. 2011 Sep 29;6(10):1656-68.
- A comparison of the epigenomes of pluripotent and lineage-committed hESCs, a comparison of the epigenomes of pluripotent and lineage-committed hESCs, Hawkins et al. Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell, 2010. 6(5):479-491.
- Epigenomic data sets such as those mentioned above can be used to predict cell-type specific enhancer elements. Recent suggests that disease SNP variants identified by GWAS are frequently positioned in enhancer elements active in cell types relevant to the disease. Mapping and analysis of chromatin state dynamics in nine human cell types. Ernst et al. Nature. 2011 May 5;473(7345):43-9.
Selected addtitional epigenomic program publications
- Identification of 67 new histone modifications and discovery that one of these, lysine crotonylation, marks active promoters and enhancers as well as testis-specific genes. The functions of many of these marks are completely unknown. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Tan et al. Cell. 2011 Sep 16;146(6):1016-28.
- The development of a strategy for affinity pulldown of tagged nucleosomes containing newly synthesized histones, allows the rates of histone turnover to be measured throughout the genome. Deal et al. Genome-wide kinetics of nucleosome turnover determined by metabolic labeling of histones. Science, 2010. May 28;328(5982):1161-4.
- Multiplex padlock probes used to capture bisulfite converted DNA allowing efficient and inexpensive identification of DNA methylation sites only in genomic regions of interest to the investigator. Deng et al. Targeted bisulfite sequencing reveals changing in DNA methylation associated with nuclear reprogramming. Nat Biotechnol, 2009. Apr;27(4):353-60.
- Development of a method for identification of proteins and histone posttranslational modifications at a single genomic locus. ChAP-MS: A Method for Identification of Proteins and Histone Posttranslational Modifications at a Single Genomic Locus. Cell Rep. 2012 Jul 26;2(1):198-205.