生物谷：虽然一个多细胞生物内的各种不同细胞类型包含同一套基因，但它们却具有很不相同的行为。这些细胞状态被认为与染色质状态有关，也就是说，与组蛋白和包裹基因组的其他蛋白的修饰有关。现在，单分子测序技术被用来构建小鼠胚胎干细胞和其他两种在发育上更先进的细胞类型的染色质状态图，从而显示了重要染色质修饰在整个基因组范围内的分布。该研究为将综合染色质甄别方法应用于对各种不同的哺乳动物细胞群、包括癌症等疾病中所出现的异常细胞发育情况进行定性研究提供了一个框架。
原始出处:
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
Broad Institute of Harvard and MIT,
Division of Health Sciences and Technology, MIT, and
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
Department of Neurology, Children's Hospital, and
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
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).
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.
