西亚试剂：Genome-scale DNA methylation maps of pluripotent and differ

发布时间：2026-03-03

Genome-scale DNA methylation maps of pluripotent and differentiated cells

Alexander Meissner^1,^2,^3,⁹, Tarjei S. Mikkelsen^2,^4,⁹, Hongcang Gu², Marius Wernig¹, Jacob Hanna¹, Andrey Sivachenko², Xiaolan Zhang², Bradley E. Bernstein^2,^5,⁶, Chad Nusbaum², David B. Jaffe², Andreas Gnirke², Rudolf Jaenisch^1,⁷ & Eric S. Lander^1,^2,^7,⁸

1 Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA
2 Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
3 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA
4 Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
5 Molecular Pathology Unit and Center for Cancer Research, MGH, Charlestown, Massachusetts 02129, USA
6 Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
7 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
8 Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02114, USA
These authors contributed equally to this work.

DNA methylation is essential for normal development^1,^2,³ and has been implicated in many pathologies including cancer^4,⁵. 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 sequencing⁶ 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.

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