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

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. Although they contain the same set of genes, different cell types in a multicellular organism maintain very different behaviours. These cell states are thought to be related to chromatin state — that is, modifications to histones and other proteins that package the genome. Single-molecule sequencing technology has now been used to construct chromatin-state maps for mouse embryonic stem cells and two other more developmentally advanced cell types, revealing the genome-wide distribution of important chromatin modifications. The study provides pointers for the use of chromatin profiling on mammalian cell populations, including those of abnormal cells, such as cancer. Single-molecule-based sequencing technology is applied to generate genome-wide maps of chromatin modifications in mammalian cells. Histone marks can discriminate genes that are active, poised for activation, or stably repressed and therefore reflect cell state and developmental potential.