Genome-scale DNA methylation maps of pluripotent and differentiated cells
Alexander Meissner,Tarjei S. Mikkelsen,Tarjei S. Mikkelsen,Hongcang Gu,Marius Wernig,Jacob H. Hanna,Andrey Sivachenko,Xiaolan Zhang,Bradley E. Bernstein,Bradley E. Bernstein,Chad Nusbaum,David B. Jaffe,Andreas Gnirke,Rudolf Jaenisch,Eric S. Lander +14 more
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TLDR
Low-throughput reduced representation bisulphite sequencing is established as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine.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.read more
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DNA methylation and methylcytosine oxidation in cell fate decisions.
TL;DR: With the advent of next-generation quantitative base-resolution maps of 5-methylcytosine and its oxidized derivatives and better coverage of the genome, the authors expect to learn more about the true significance of these DNA modifications in the regulation of cell fate choices.
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Specificity, propagation, and memory of pericentric heterochromatin
Katharina Müller-Ott,Fabian Erdel,Anna Matveeva,Jan-Philipp Mallm,Anne Rademacher,Matthias Hahn,Caroline Bauer,Qin Zhang,Sabine Kaltofen,Gunnar Schotta,Thomas Höfer,Karsten Rippe +11 more
TL;DR: A predictive mathematical model is developed that explains how chromatin‐bound SUV39H1/2 complexes act as nucleation sites and propagate a spatially confined PCH domain with elevated histone H3 lysine 9 trimethylation levels via chromatin dynamics, which makes it an attractive model for establishing functional epigenetic domains throughout the genome.
Journal ArticleDOI
DNA methylation profiles define stem cell identity and reveal a tight embryonic-extraembryonic lineage boundary.
Claire E. Senner,Claire E. Senner,Felix Krueger,David Oxley,Simon Andrews,Myriam Hemberger,Myriam Hemberger +6 more
TL;DR: Detailed methylation profiles identify a cohort of developmentally regulated sequence elements that will be most valuable to uncover novel transcriptional regulators and pivotal “gatekeeper” genes in pluripotency and lineage differentiation.
Journal ArticleDOI
Germline-derived DNA methylation and early embryo epigenetic reprogramming: The selected survival of imprints
TL;DR: The processes involved in epigenetic reprograming and the mechanisms that ensure allelic methylation at imprinted loci is retained throughout the life of the organism are examined, discussing the critical differences between mouse and humans.
Journal ArticleDOI
DNA methylation data analysis and its application to cancer research
TL;DR: This paper briefly reviews the molecular techniques that generate DNA methylation data and its application to cancer studies, and describes the coverage of the methylome by the most recent version of Infinium HumanMethylation450 BeadChip technology.
References
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DNA methylation patterns and epigenetic memory
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Journal ArticleDOI
A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells
Bradley E. Bernstein,Tarjei S. Mikkelsen,Tarjei S. Mikkelsen,Xiaohui Xie,Michael Kamal,Dana J. Huebert,James Cuff,Ben Fry,Alexander Meissner,Marius Wernig,Kathrin Plath,Rudolf Jaenisch,Alexandre Wagschal,Robert Feil,Stuart L. Schreiber,Stuart L. Schreiber,Eric S. Lander,Eric S. Lander +17 more
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Journal ArticleDOI
Genome-wide maps of chromatin state in pluripotent and lineage-committed cells
Tarjei S. Mikkelsen,Manching Ku,Manching Ku,David B. Jaffe,Biju Issac,Biju Issac,Erez Lieberman Aiden,Erez Lieberman Aiden,Georgia Giannoukos,Pablo Alvarez,William Brockman,Tae Kyung Kim,Richard Koche,Richard Koche,Richard Koche,William Lee,Eric M. Mendenhall,Eric M. Mendenhall,Aisling O'Donovan,Aviva Presser,Carsten Russ,Xiaohui Xie,Alexander Meissner,Marius Wernig,Rudolf Jaenisch,Chad Nusbaum,Eric S. Lander,Eric S. Lander,Bradley E. Bernstein,Bradley E. Bernstein +29 more
TL;DR: The application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells is reported and it is shown that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms.
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TL;DR: Insight is given into the connections between chromatin modifications and transcriptional regulatory activity and a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2) is uncovered, providing a new tool for the functional annotation of the human genome.
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