Article

Nature 448, 553-560 (2 August 2007) | doi:10.1038/nature06008; Received 10 May 2007; Accepted 13 June 2007; Published online 1 July 2007

Genome-wide maps of chromatin state in pluripotent and lineage-committed cells

Tarjei S. Mikkelsen1,2, Manching Ku1,4, David B. Jaffe1, Biju Issac1,4, Erez Lieberman1,2, Georgia Giannoukos1, Pablo Alvarez1, William Brockman1, Tae-Kyung Kim5, Richard P. Koche1,2,4, William Lee1, Eric Mendenhall1,4, Aisling O'Donovan4, Aviva Presser1, Carsten Russ1, Xiaohui Xie1, Alexander Meissner3, Marius Wernig3, Rudolf Jaenisch3, Chad Nusbaum1, Eric S. Lander1,3,7 & Bradley E. Bernstein1,4,6,7

  1. Broad Institute of Harvard and MIT,
  2. Division of Health Sciences and Technology, MIT, and
  3. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
  4. Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
  5. Department of Neurology, Children's Hospital, and
  6. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
  7. These authors contributed equally to this work.

Correspondence to: Eric S. Lander1,3,7Bradley E. Bernstein1,4,6,7 Correspondence and requests for materials should be addressed to E.S.L. (Email: lander@broad.mit.edu) or B.E.B. (Email: bbernstein@partners.org).

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We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells. By obtaining over four billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse embryonic stem cells, neural progenitor cells and embryonic fibroblasts. We find that lysine 4 and lysine 27 trimethylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential. Lysine 36 trimethylation marks primary coding and non-coding transcripts, facilitating gene annotation. Trimethylation of lysine 9 and lysine 20 is detected at satellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences. Lysine 4 and lysine 9 trimethylation marks imprinting control regions. Finally, we show that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms. This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations.

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