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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From neural development to cognition: unexpected roles for chromatin
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TL;DR: This work focuses on the dynamics of PcG protein complex action during cell fate transitions and on the implications of histone modifications for cell lineage commitment.
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Passive and active DNA methylation and the interplay with genetic variation in gene regulation
Maria Gutierrez-Arcelus,Maria Gutierrez-Arcelus,Tuuli Lappalainen,Tuuli Lappalainen,Stephen B. Montgomery,Stephen B. Montgomery,Alfonso Buil,Alfonso Buil,Halit Ongen,Halit Ongen,Alisa Yurovsky,Alisa Yurovsky,Julien Bryois,Julien Bryois,Thomas Giger,Luciana Romano,Luciana Romano,Alexandra Planchon,Alexandra Planchon,Emilie Falconnet,Deborah Bielser,Maryline Gagnebin,Ismael Padioleau,Ismael Padioleau,Christelle Borel,Audrey Letourneau,Periklis Makrythanasis,Michel Guipponi,Corinne Gehrig,Stylianos E. Antonarakis,Emmanouil T. Dermitzakis,Emmanouil T. Dermitzakis +31 more
TL;DR: It is shown that unlike genetic regulatory variation, DNA methylation alone does not significantly drive allele specific expression, and inferred mechanistic relationships using genetic variation as well as correlations with TF abundance reveal both a passive and active role of DNAmethylation to regulatory interactions influencing gene expression.
Journal ArticleDOI
GC-Rich Sequence Elements Recruit PRC2 in Mammalian ES Cells
Eric M. Mendenhall,Richard Koche,Thanh Truong,Thanh Truong,Thanh Truong,Vicky Weijie Zhou,Biju Issac,Biju Issac,Biju Issac,Andrew S. Chi,Manching Ku,Manching Ku,Manching Ku,Bradley E. Bernstein,Bradley E. Bernstein,Bradley E. Bernstein +15 more
TL;DR: In this paper, a series of engineered bacterial artificial chromosomes were integrated into embryonic stem (ES) cells and examined their chromatin, and it was shown that a 44 kb region corresponding to the Zfpm2 locus initiates de novo recruitment of PRC2.
Journal ArticleDOI
Regulation of Stem Cell Pluripotency and Differentiation Involves a Mutual Regulatory Circuit of the Nanog, OCT4, and SOX2 Pluripotency Transcription Factors With Polycomb Repressive Complexes and Stem Cell microRNAs
Vasundhra Kashyap,Naira C. Rezende,Kymora B. Scotland,Sebastian Shaffer,Jenny L. Persson,Lorraine J. Gudas,Nigel P. Mongan +6 more
TL;DR: How aberrant functioning of components of the stem cell regulatory network may contribute to malignant transformation of adult stem cells and the establishment of a "cancer stem cell" phenotype and thereby underlie multiple types of human malignancies is described.
References
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