title: Genome-scale DNA methylation maps of pluripotent and differentiated cells.
abstract: DNA methylation is essential for normal development and has been implicated in many pathologies including cancer. Our knowledge about the genome-wide distribution of DNA methylation, how it changes during cellular differentiation and how it relates to histone methylation and other chromatin modifications in mammals remains limited. Here we report the generation and analysis of genome-scale DNA methylation profiles at nucleotide resolution in mammalian cells. Using high-throughput reduced representation bisulphite sequencing and single-molecule-based sequencing, we generated DNA methylation maps covering most CpG islands, and a representative sampling of conserved non-coding elements, transposons and other genomic features, for mouse embryonic stem cells, embryonic-stem-cell-derived and primary neural cells, and eight other primary tissues. Several key findings emerge from the data. First, DNA methylation patterns are better correlated with histone methylation patterns than with the underlying genome sequence context. Second, methylation of CpGs are dynamic epigenetic marks that undergo extensive changes during cellular differentiation, particularly in regulatory regions outside of core promoters. Third, analysis of embryonic-stem-cell-derived and primary cells reveals that 'weak' CpG islands associated with a specific set of developmentally regulated genes undergo aberrant hypermethylation during extended proliferation in vitro, in a pattern reminiscent of that reported in some primary tumours. More generally, the results establish reduced representation bisulphite sequencing as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine.
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.forename: Tarjei S
authors.initials: TS
authors.lastname: Mikkelsen
authors.forename: Hongcang
authors.initials: H
authors.lastname: Gu
authors.forename: Marius
authors.initials: M
authors.lastname: Wernig
authors.forename: Jacob
authors.initials: J
authors.lastname: Hanna
authors.forename: Andrey
authors.initials: A
authors.lastname: Sivachenko
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
authors.forename: Chad
authors.initials: C
authors.lastname: Nusbaum
authors.forename: David B
authors.initials: DB
authors.lastname: Jaffe
authors.forename: Andreas
authors.initials: A
authors.lastname: Gnirke
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D017124:Conserved Sequence; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D016678:Genome / Q000235:genetics; D023281:Genomics; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: D006657:Histones