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. Lander^1,3,7Bradley E. Bernstein^1,4,6,7 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).

Abstract

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.

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. Lander^1,3,7Bradley E. Bernstein^1,4,6,7 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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