The Reference Epigenome Mapping Centers (REMC) will aim to transform our understanding of human epigenetics through production and integrative analysis of comprehensive reference epigenomes for ES cells, differentiated cells and tissues. In pursuit of this goal, we have assembled a unique scientific team and infrastructure with broad expertise and capabilities in stem cell biology, epigenomics, technology, production research and computation. We recently demonstrated two complementary methods that leverage ultra high-throughput sequencing for epigenomic analysis. In the first method, genome-wide chromatin maps are acquired by deep sequencing chromatin IP DNA (ChlP-Seq). In the second, nucleotide-resolution DNA methylation maps are generated by high-throughput bisulfite-sequencing (HTBS). These methods represent major improvements over prior tools as they yield precise digital information, have high genome coverage, require fewer cells and are cost-effective. Multiple epigenomic maps have already been produced for stem cells and primary tissues, and pipelines have been assembled for efficient data collection, processing and analysis. For the REMC project, we propose to apply ChlP-Seq and HTBS pipelines to generate comprehensive high-resolution maps of chromatin state and DNA methylation for 100 diverse cell types. Cell types were selected for their biological and medical importance, and for their potential to maximize the comprehensiveness of acquired epigenomic data. They include human ES cells, ES-derived cells, mesenchymal stem cells, reprogrammed stem cells and primary tissues. ChlP-Seq will be used to map highly informative chromatin modifications and related chromatin proteins in each cell type. HTBS will be used to generate nucleotide-resolution DNA methylation maps. Reference epigenomes will reveal the locations and activation states of diverse functional genomic elements, inform on the developmental state and potential of studied cell populations, and provide a framework for understanding complex epigenetic regulatory mechanisms. All data will be made available to the scientific community upon verification.

Public Health Relevance

Comprehensive characterization of epigenetic marks ('the epigenome') is a critical step towards a global understanding of the human genome in health and disease. The proposed mapping studies will provide unprecedented views of the human epigenetic landscape and its variation across cell states, offer fundamental insight into the functions and interrelationships of epigenetic marks, and provide a framework for future studies of normal and diseased epigenomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01ES017155-05
Application #
8311844
Study Section
Special Emphasis Panel (ZRG1-CB-P (50))
Program Officer
Tyson, Frederick L
Project Start
2008-09-29
Project End
2013-09-30
Budget Start
2012-07-01
Budget End
2013-09-30
Support Year
5
Fiscal Year
2012
Total Cost
$3,186,072
Indirect Cost
$402,585
Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Ziller, Michael J; Hansen, Kasper D; Meissner, Alexander et al. (2015) Coverage recommendations for methylation analysis by whole-genome bisulfite sequencing. Nat Methods 12:230-2, 1 p following 232
Farh, Kyle Kai-How; Marson, Alexander; Zhu, Jiang et al. (2015) Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518:337-43
Knoechel, Birgit; Roderick, Justine E; Williamson, Kaylyn E et al. (2014) An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet 46:364-70
Smith, Zachary D; Chan, Michelle M; Humm, Kathryn C et al. (2014) DNA methylation dynamics of the human preimplantation embryo. Nature 511:611-5
Lunnon, Katie; Smith, Rebecca; Hannon, Eilis et al. (2014) Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nat Neurosci 17:1164-70
De Jager, Philip L; Srivastava, Gyan; Lunnon, Katie et al. (2014) Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 17:1156-63
Smith, Zachary D; Meissner, Alexander (2013) DNA methylation: roles in mammalian development. Nat Rev Genet 14:204-20
Herlofsen, Sarah R; Bryne, Jan Christian; Hoiby, Torill et al. (2013) Genome-wide map of quantified epigenetic changes during in vitro chondrogenic differentiation of primary human mesenchymal stem cells. BMC Genomics 14:105
Mendenhall, Eric M; Williamson, Kaylyn E; Reyon, Deepak et al. (2013) Locus-specific editing of histone modifications at endogenous enhancers. Nat Biotechnol 31:1133-6
Gifford, Casey A; Ziller, Michael J; Gu, Hongcang et al. (2013) Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell 153:1149-63

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