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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We thank S. Fisher, M. Kellis, B. Birren and M. Zody for technical assistance and constructive discussions. We acknowledge L. Zagachin in the MGH Nucleic Acid Quantitation core for assistance with real-time PCR. E.M. was supported by an institutional training grant from NIH. M.W. was supported by fellowships from the Human Frontiers Science Organization Program and the Ellison Foundation. This research was supported by funds from the National Human Genome Research Institute, the National Cancer Institute, the Burroughs Wellcome Fund, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard.
All analysed data sets can be obtained from http://www.broad.mit.edu/seq_platform/chip/. Microarray data have been submitted to the GEO repository under accession number GSE8024.
This file contains Supplementary Table 1 which includes the list of datasets analyzed.
This file contains Supplementary Table 2 which includes the primers for RT-PCR validation of ChIP-Seq.
This file contains Supplementary Table 3 which includes the list of analyzed promoters and their chromatin state in ES cells, neural progenitors and embryonic fibroblasts.
This file contains Supplementary Table 4 which includes the expression levels for analyzed genes in ES cells, neural progenitors and embryonic fibroblasts.
This file contains Supplementary Table 5 which includes the Gene Ontology categories associated with monovalent and bivalent promoters in ES cells.
This file contains Supplementary Table 6 which includes the chromatin state of promoters associated with known regulators or markers of differentiated cell types
This file contains Supplementary Table 7 which includes the allelic bias observed at verified or putative imprinting control regions.
About this article
Endogenous Retroviruses Function as Gene Expression Regulatory Elements During Mammalian Pre-implantation Embryo Development
International Journal of Molecular Sciences (2019)