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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Excision of Reprogramming Transgenes Improves the Differentiation Potential of iPS Cells Generated with a Single Excisable Vector
Cesar Sommer,Andreia Gianotti Sommer,Tyler A. Longmire,Constantina Christodoulou,Dolly D. Thomas,Monica Gostissa,Frederick W. Alt,George J. Murphy,Darrell N. Kotton,Gustavo Mostoslavsky +9 more
TL;DR: It is found that removal of the reprogramming vector markedly improves the developmental potential of iPS cells and significantly augments their capacity to undergo directed differentiation in vitro.
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DNA methylation: TET proteins—guardians of CpG islands?
TL;DR: In this paper, the TET proteins have an important role in regulating DNA methylation fidelity, and that their inactivation contributes to the DNA hypermethylation phenotype often observed in cancer.
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Distinct Properties of Cell-Type-Specific and Shared Transcription Factor Binding Sites
Jason Gertz,Daniel Savic,Katherine E. Varley,E. Christopher Partridge,Alexias Safi,Preti Jain,Gregory M. Cooper,Timothy E. Reddy,Gregory E. Crawford,Richard M. Myers +9 more
TL;DR: The authors used an integrative approach to study estrogen receptor α (ER) and found that ER exhibits two distinct modes of binding, i.e., shared sites, bound in multiple cell types, are characterized by high-affinity estrogen response elements (EREs), inaccessible chromatin, and a lack of DNA methylation, while cell-specific sites, characterized by lack of EREs, co-occurrence with other transcription factors, and cell-type-specific chromatin accessibility and DNA methylization.
Journal ArticleDOI
Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells
Grant A. Challen,Deqiang Sun,Allison Mayle,Mira Jeong,Min Luo,Benjamin Rodriguez,Cates Mallaney,Hamza Celik,Liubin Yang,Zheng Xia,Sean M Cullen,Jonathan S. Berg,Yayun Zheng,Gretchen J. Darlington,Wei Li,Margaret A. Goodell +15 more
TL;DR: Conditional inactivation of Dnmt3b in HSCs either alone or combined with Dn mt3a deletion was synergistic, resulting in enhanced HSC self-renewal and a more severe block in differentiation than in DnMT3a-null cells, whereas loss of Dmnt3b resulted in a mild phenotype.
Journal ArticleDOI
Cell type–specific DNA methylation at intragenic CpG islands in the immune system
Aimee M. Deaton,Shaun Webb,Alastair R.W. Kerr,Robert S. Illingworth,Jacky Guy,Robert J. Andrews,Adrian Bird +6 more
TL;DR: The results indicate that DNA methylation changes play a relatively minor role in the late stages of differentiation and suggest that intragenic CGIs represent regulatory sites of differential gene expression during the early stages of lineage specification.
References
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