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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TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells.
Nipun Verma,Nipun Verma,Heng Pan,Louis C. Dore,Abhijit Shukla,Qing V. Li,Qing V. Li,Bobbie Pelham-Webb,Virginia Teijeiro,Virginia Teijeiro,Federico Gonzalez,Andrei V. Krivtsov,Chan Jung Chang,Eirini P. Papapetrou,Chuan He,Olivier Elemento,Danwei Huangfu +16 more
TL;DR: It is concluded that TET proteins safeguard bivalent promoters from de novo methylation to ensure robust lineage-specific transcription upon differentiation.
Journal ArticleDOI
Developmental programming and epigenetics
TL;DR: This article focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, positions, and functions of epigenetic marks.
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Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis
Henne Holstege,Wayne Pfeiffer,Daoud Sie,Marc Hulsman,Thomas J. Nicholas,Clarence Lee,Tristen Ross,Jue Lin,Mark A. Miller,Bauke Ylstra,Hanne Meijers-Heijboer,Martijn H. Brugman,Frank J. T. Staal,Gert Holstege,Marcel J. T. Reinders,Timothy T. Harkins,Samuel Levy,Erik A. Sistermans +17 more
TL;DR: The distribution of variant allele frequencies of these mutations suggest that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones, which suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematobiology clonal evolution at extreme ages.
Journal ArticleDOI
DNA methylation based biomarkers: practical considerations and applications.
TL;DR: The objective of this review is to discuss the advantages of DNA methylation as a biomarker, the practical considerations for their development, and their use in disease detection, prediction of outcome or treatment response, through multiple examples mainly focusing on cancer, but also to evoke their potential for complex diseases and prenatal diagnostics.
Journal ArticleDOI
A statistical framework for modeling gene expression using chromatin features and application to modENCODE datasets
Chao Cheng,Koon-Kiu Yan,Kevin Y. Yip,Kevin Y. Yip,Joel Rozowsky,Roger P. Alexander,C. Shou,Mark Gerstein +7 more
TL;DR: A statistical framework is developed to study the relationship between chromatin features and gene expression that can be used to predict gene expression of protein coding genes, as well as microRNAs, including modENCODE worm datasets.
References
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DNA methylation patterns and epigenetic memory
TL;DR: The heritability of methylation states and the secondary nature of the decision to invite or exclude methylation support the idea that DNA methylation is adapted for a specific cellular memory function in development.
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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